A 70-year-old Chinese woman was diagnosed with stage IV anaplastic lymphoma kinase (ALK)–positive non–small-cell lung carcinoma with intrapulmonary, pleural and lymph node metastasis in December 2022. Her private oncologist first prescribed lorlatinib in mid-December 2022. The drug had been well tolerated by the patient and there was no evidence of myelotoxicity.

The patient attended a public hospital for further care in February 2023. Lorlatinib was switched to alectinib on 17 March 2023. Her baseline haemoglobin level was 11.1 g/dL on 16 March 2023 prior to commencement of alectinib. Subsequent follow-ups on 13 April and 3 May revealed that her haemoglobin level had fallen to 10 g/dL and 8.7 g/dL, respectively (Fig 1a). Mean cell volume was 65.4 fL. She had no clinical signs or symptoms suggestive of acute blood loss.

Peripheral blood smear showed marked red cell sphero-acanthocytosis (Fig 2). The previously normal bilirubin level rose to 43 μmol/L and lactate dehydrogenase (LDH) level to 317 IU/L. Haptoglobin level was very low (<0.06 g/L) [Fig 1b]. Direct Coombs test (DAT) was negative. Alectinib had been withheld since 3 May 2023 in view of the potential differential diagnosis of drug-induced haemolytic anaemia. After suspending alectinib, the haemoglobin level remained static for 1 week (8.7 g/dL on 10 May 2023). It then increased slowly over the following week (9.1 g/dL on 15 May 2023) [Fig 1a]. Lactate dehydrogenase level also decreased to 278 IU/L, with total bilirubin level decreased to 24 μmol/L and direct bilirubin level normalised (Fig 1b).

Since the anaemia of the patient had improved, another ALK inhibitor, brigatinib, was prescribed on 18 May 2023, at 90 mg daily. Her haemoglobin level increased to 9.7 g/dL after 2 weeks. Total bilirubin level was normalised on 1 June 2023 (Fig 1a). Brigatinib was then stepped up to 180 mg daily (full dose) as it was well tolerated.

The patient demonstrated a favourable response to ALK inhibitors as evidenced by a continuously decreasing cancer embryonic antigen level. A contrast computed tomography scan of the thorax, abdomen and pelvis on 30 May 2023 showed partial response after 5 months of lorlatinib and alectinib. The primary lung tumour at the right lower lobe showed a partial response, decreasing from 6.2 cm to 1.5 cm in size. There was no evidence of bone metastasis.

Anaemia caused by alectinib is uncommon although clinical trials have reported clinically significant anaemia (grade ≥3) in around 7% of cases.1 Nonetheless there are limited reports of alectinib-induced haemolytic anaemia.2 Misawa et al3 described a case of grade 4 anaemia due to drug-induced haemolytic anaemia in 2023. No such case has been reported in Hong Kong to date.

The index patient demonstrated alectinib-induced haemolytic anaemia with morphological change to erythrocytes and negative DAT result. The blood smear of sphero-acanthocytosis combined with altered bilirubin, LDH and haptoglobin was strongly suggestive of haemolytic anaemia. The improvement in haemoglobin, bilirubin and LDH levels following suspension of alectinib suggested that the haemolytic anaemia was drug induced.

Drug-induced haemolytic anaemia is usually due to drug-induced immune haemolytic anaemia.4 Nonetheless in this case, an autoimmune cause was excluded due to the patient’s negative DAT result even though 5% to 10% of DAT-negative cases may have an immune component.2 Differential diagnoses of DAT-negative haemolytic anaemia include membranopathies (eg, hereditary spherocytosis), thrombotic microangiopathies (eg, thrombotic thrombocytopenic purpura), enzymopathies (eg, glucose-6-phosphate dehydrogenase), infection (eg, malaria or Clostridium), and haemoglobinopathies (eg, sickle cell disease).5 Our patient had no signs of infection or history of haematological disease. The temporal relationship between administration of alectinib and the occurrence of haemolytic anaemia favoured a diagnosis of drug-induced haemolysis. The laboratory findings were also consistent with other case reports.6

The precise mechanism is uncertain. It has been postulated that alectinib induces erythrocyte membrane changes.3 The presence of spherocytes in the peripheral blood film may arise from these membrane changes (Fig 2). Additional investigation is warranted to further understand the underlying mechanism.

Our patient developed haemolytic anaemia within 2 months of commencing alectinib. Misawa et al3 reported that grade 4 haemolytic anaemia could occur after 3 years. Regular monitoring of haemoglobin should be undertaken in patients prescribed alectinib. Haemolytic anaemia workup, including peripheral blood smear, bilirubin, haptoglobin and LDH levels, should be considered if indicated.

This case demonstrated no cross reactivity among other ALK-positive first-line targeted therapies (lorlatinib and brigatinib). Our patient first commenced lorlatinib following a private consultation and later switched to alectinib with funding support. The patient continues her treatment with brigatinib. There was no documented drop in haemoglobin level after lorlatinib, and following discontinuation of alectinib and initiation of brigatinib, her haemoglobin level showed an improving trend. Limited case reports of alectinib-induced haemolytic anaemia have been managed by discontinuation of therapy or rechallenge with alectinib at a reduced dosage.2 3 6 To the best of our knowledge, cross reactivity among first-line ALK tyrosine inhibitors (lorlatinib, alectinib and brigatinib) has not been reported. Our case demonstrates that it is safe to switch treatment to an alternative ALK inhibitor when alectinib-induced haemolytic anaemia occurs. The drug-induced haemolytic anaemia is specific to alectinib.

This case highlights the importance of interval haemoglobin monitoring. A persistent drop in haemoglobin level following initiation of alectinib warrants prompt investigations for possible differential diagnosis of alectinib-induced haemolytic anaemia. This case also suggests that it is safe to switch to an alternative ALK inhibitor in the presence of alectinib-induced haemolytic anaemia.

Both authors contributed to the concept or design of the study, acquisition of the data, analysis or interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Both authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Both authors have disclosed no conflicts of interest.

The authors thank Dr Kenneth Mung from the Department of Pathology of Pamela Youde Nethersole Eastern Hospital for providing microscopic photos of the blood smear of the patient.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The patient provided consent for all treatments and procures, and consent for publication of this case report.

1. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non–small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:1056-64. Crossref

2. Okumoto J, Sakamoto S, Masuda T, et al. Alectinib-induced immune hemolytic anemia in a patient with lung adenocarcinoma. Intern Med 2021;60:611-5. Crossref

3. Misawa, K, Nakamichi S, Iida H, et al. Alectinib-induced severe hemolytic anemia in a patient with ALK-positive non–small cell lung cancer: a case report. Onco Targets Ther 2023;16:65-9. Crossref

4. Garbe E, Andersohn F, Bronder E, et al. Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study. Br J Haematol 2011;154:644-53. Crossref

5. Palmer D, Seviar D. How to approach haemolysis: haemolytic anaemia for the general physician. Clin Med (Lond) 2022;22:210-3. Crossref

6. Gullapalli V, Xu W, Lewis CR, Anazodo A, Gerber GK. A multi-centre case series of alectinib-related erythrocyte membrane changes and associated haemolysis. J Hematop 2021;14:131-6. Crossref

A 58-year-old Chinese woman with good past health presented with a 2-day history of right lower abdominal pain. Routine biochemical blood tests revealed a white blood cell count of 9.1 × 10⁹/L and normal renal function (creatinine level: 49 μmol/L). An urgent contrast-enhanced computed tomography scan revealed acute diverticulitis in the caecum. Incidentally, a solitary well-defined homogenous fat-density mass with unenhanced density of -63 Hounsfield units was evident at the right renal sinus, with extension into the right renal vein and inferior vena cava (IVC) [Fig 1]. Findings were suggestive of an aggressive renal angiomyolipoma (AML) with right renal vein and IVC thrombus. The patient was referred to an urologist. Subsequent robotic-assisted laparoscopic radical nephrectomy and IVC thrombectomy were performed uneventfully.

The surgical specimen provided by the pathologist demonstrated the right renal vein depicted as a purple red strip and fatty tumour (Fig 2a). Microscopic examination revealed all features of a typical AML including mature adipocytes, myoid spindle cells, and thick-walled blood vessels (Fig 2b). It was also positive on Melan A (Fig 2c) and HMB-45 stains (Fig 2d).

Angiomyolipoma is a common benign renal mesenchymal neoplasm composed in variable proportions of adipose tissue, smooth muscle cells, and abnormal vessels. It is most commonly sporadic (80%) or associated with genetic syndromes such as tuberous sclerosis.1 A renal mass with visualisation of macroscopic fat density on computed tomography is virtually diagnostic of AML. Therefore, visualisation of fat density in the intravascular compartment is indicative of tumour invasion.

Cases of aggressive AML with renal vein and IVC thrombus have been reported. A literature review2 of 26 cases of invasive renal AML reported that a large size and right-sided location of the tumour may be contributing factors in AML with intravascular invasion. This may be related to the shorter and straighter course of the right renal vein. Two variants of renal AML, namely, classic and epithelioid, have been described. The epithelioid variant has been reported to exhibit aggressive behaviour with IVC thrombus.3 In this case, the patient had a classic subtype of renal AML with mature adipocytes (Fig 2b) and no epithelioid cells.

The optimal treatment is robotic nephrectomy and IVC thrombectomy irrespective of tumour size, since IVC thrombus can be life threatening with higher risks of vessel occlusion and tumour embolus. A multi-institutional study in 2016 retrospectively reviewed 32 cases of robotic radical nephrectomy and IVC thrombectomy and demonstrated a favourable outcome with adequate robotic experience including less blood loss, earlier patient discharge, and fewer complications compared with open nephrectomy.4 Inferior vena cava thrombectomy follows similar surgical principles to that for renal cell carcinoma with IVC thrombus. Proper visualisation and mobilisation of the kidney, renal vein and IVC allow selective vascular clamping, namely, the infrarenal and suprarenal IVC as well as the renal vein. The IVC is then exposed and the tumour is dissected away from the IVC. The cavotomy is then closed and nephrectomy is performed.

We describe a classic subtype of renal AML extending into the renal vein and IVC, managed by robotic-assisted laparoscopic nephrectomy and IVC thrombectomy. Computed tomography and other imaging modalities are essential to diagnose AML and for proper surgical planning. With proper visualisation of the kidney, renal vein and IVC, a safe and successful outcome of robotic nephrectomy and IVC thrombectomy is achieved.

Concept or design: PHW Lo, HM Kwok, FH Ng, JKF Ma.
Acquisition of data: PHW Lo, HM Kwok, FH Ng, HY Lo.
Analysis or interpretation of data: PHW Lo, HM Kwok, HY Lo.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Kowloon West Cluster Research Ethics Committee of Hospital Authority, Hong Kong [Ref No.: KW/EX-23-010(180-06)]. The patient has given a consent statement for publication of this case report.

1. Martignoni G, Amin M.B. Pathology and genetics of tumours of the urinary system and male genital organs. In: Ebie JN, Sauter G, Epstein JI, editors. World Health Organization Classification of Tumours. Lyon, France: IARC; 2004: 65-7.

2. Islam AH, Ehara T, Kato H, Hayama M, Kashiwabara T, Nishizawa O. Angiomyolipoma of kidney involving the inferior vena cava. Int J Urol 2004;11:897-902. Crossref

3. Fox C, Salami SS, Moreira DM, et al. Aggressive renal angiomyolipoma of the lipomatous variant with inferior vena cava thrombus: a case report and review of the literature. Urol Case Rep 2013;2:9-11. Crossref

4. Abaza R, Shabsigh A, Castle E, et al. Multi-institutional experience with robotic nephrectomy with inferior vena cava tumor thrombectomy. J Urol 2016;195:865-71. Crossref

We report the first case of atypical fifth metatarsal fracture in a 69-year-old Chinese woman following long-term treatment for osteoporosis with denosumab. She had been diagnosed with hypertension in 2007 and was managed with amlodipine and losartan. One year previously in 2006, she had been diagnosed with postmenopausal osteoporosis based on low bone mineral density (BMD) revealed at a health screening. Her height and weight were 150 cm and 54 kg, respectively, with a body mass index of 24.0 kg/m². She had no previous history of fracture or parental history of hip fracture.

The patient was initially prescribed raloxifene for 2 years but due to a suboptimal BMD response, she was treated with alendronate for 4 years. Given the prolonged use of alendronate, she was switched to strontium ranelate but this was discontinued a few months later due to intolerance. Dual-energy X-ray absorptiometry at that juncture in 2014 showed the BMD of the L1-L4 level, the left femoral neck, and the left total hip were 0.928 g/cm² (T-score=-2.1), 0.646 g/cm² (T-score=-2.9), and 0.725 g/cm² (T-score=-2.4), respectively. She was started on subcutaneous denosumab 60 mg every 6 months that was continued until October 2021. Her most recent dual-energy X-ray absorptiometry in December 2020 revealed the BMD of the left femoral neck and left total hip were 0.544 g/cm² (T-score=-2.3) and 0.715 g/cm² (T-score=-1.4), respectively, indicating significant improvement. The BMD of the lumbar spine was not reported due to significant degenerative changes.

The patient presented to the primary care physician in November 2021 with a 2-week history of mechanical right lateral foot pain. She reported no preceding injury but physical examination revealed mild tenderness over the base of the right fifth metatarsal. There was no joint effusion or signs of infection and distal neurovascular status was intact. X-ray of the right foot was performed (Fig a) and she was prescribed analgesics for right foot tendinitis. One month later in December 2021, she complained of persistent right foot pain during her scheduled follow-up at the Osteoporosis Centre of The University of Hong Kong. Physical examination revealed intense tenderness over the lateral side of her right foot, near the base of the fifth metatarsal. Review of the X-ray taken in November 2021 identified beaking over the lateral aspect at the base of the right fifth metatarsal, indicating a periosteal reaction, associated with a transverse radiolucency across the cortex. Repeat X-ray of the right foot (Fig b) revealed a more prominent transverse radiolucency across the same site. A diagnosis of denosumab-related atypical metatarsal fracture was reached given the long duration of antiresorptive treatment (likely related to denosumab since fracture occurred after 7 years of denosumab), prodromal symptoms and absence of high-energy trauma, along with characteristic radiological findings. Blood tests showed serum calcium level of 2.44 mmol/L (reference range, 2.24-2.63), phosphate level of 0.98 mmol/L (reference range, 0.88-1.45), creatinine level of 60 μmol/L (reference range, 49-82), parathyroid hormone level of 1.7 pmol/L (reference range, 1.3-6.8), and 25-hydroxyvitamin level of 70 nmol/L (sufficient level: 50-220). Although bone turnover markers were not measured, serum alkaline phosphatase level was on the low side at 48 U/L (reference range, 47-124) that could suggest suppressed bone turnover. An X-ray of the left foot was not available, but the patient had no history of left foot pain. For her atypical right metatarsal fracture, she was given a short leg plaster and completed a course of physiotherapy. The fracture healed completely in 6 months. She was started on teriparatide as anti-osteoporosis treatment, and this was tolerated well.

The American Society for Bone and Mineral Research Task Force published a report in 2014 on the case definition of atypical femoral fracture (AFF),1 which refers to fracture located along the femoral diaphysis just distal to lesser trochanter to just proximal to the supracondylar flare. Major and minor diagnostic criteria were proposed. The pathophysiology is postulated to be related to oversuppression of bone turnover impairing normal bone remodelling in response to physiological stress. Prolonged bisphosphonate use has been associated with rare adverse events of atypical fractures (3.2-50 cases per 100 000 person-years).1 Atypical femoral fractures related to denosumab use have been reported, but they are even rarer (0.8 per 10000 person-years).2 Our patient had been taking alendronate for 4 years and denosumab for 7 years. It was very likely that bone turnover had been severely suppressed. In line with this, her serum alkaline phosphatase level was at the lower end of the reference range.

Less commonly, atypical fractures involving long bones other than the femur have also been reported among patients prescribed bisphosphonate or denosumab, including the tibia and ulnar.3 Notably, atypical metatarsal fractures associated with bisphosphonate use for osteoporosis have been reported in only three cases.3 4 5 Our case is the first of atypical metatarsal fracture associated with denosumab. Atypical metatarsal fractures associated with antiresorptive agents, as illustrated in our patient and other case reports (Table), share several characteristics and are distinct from typical fifth metatarsal fractures. They were all associated with prodromal pain with no history of high-energy impact. More importantly, the radiological features fulfil some of the criteria of AFF proposed in the American Society for Bone and Mineral Research 2013 consensus,1 including a fracture line originating in the lateral cortex and periosteal reaction. Although the atypical metatarsal fracture in our patient was temporally related to the long duration of denosumab, the possibility that alendronate had caused abnormal microarchitecture that persisted and was perpetuated by denosumab therapy could not be excluded since she had also been prescribed alendronate for 4 years.

When AFF is diagnosed, antiresorptive agents should be stopped. The risk of AFF of the contralateral femur declines after discontinuation of bisphosphonate. Adequate vitamin D, calcium supplementation and teriparatide can promote healing and reunion of atypical femoral fracture. Surgery promotes healing and relieves pain for AFF. Incomplete AFF has been successfully treated with prophylactic intramedullary nailing. Unlike AFF, the treatment for atypical metatarsal fractures is less well defined. The decision about treatment involves a patient-physician discussion, although the presence of a longer transverse radiolucent line across the shaft favours surgical management.

Although bisphosphonate and denosumab are safe and efficacious, rare side-effects of atypical fractures have been reported. Our case highlights the importance of clinician vigilance for atypical fractures when patients on long-term antiresorptive agents complain of pain over the long bones (not limited to the femur) to enable timely management to reduce morbidities and re-evaluate the anti-osteoporosis strategy.

Concept or design: All authors.
Acquisition of data: EKH Leung, AKC Kan, YC Woo, DTW Lui.
Analysis or interpretation of data: EKH Leung, AKC Kan, SCW Cheung, YC Woo, DTW Lui.
Drafting of the manuscript: EKH Leung, AKC Kan, YC Woo, DTW Lui.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. Informed consent was obtained from the patient for publication of this case report and any accompanying images.

1. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014;29:1-23. Crossref

2. Paparodis R, Buehring B, Pelley EM, Binkley N. A case of an unusual subtrochanteric fracture in a patient receiving denosumab. Endocr Pract 2013;19:e64-8. Crossref

3. Min BC, Chung CY, Park MS, Sung KH, Lee KM. A suspicious atypical fracture of 5th metatarsal bone: a case report. J Orthop Sci 2022;27:281-3. Crossref

4. Pradhan P, Saxena V, Yadav A, Mehrotra V. Atypical metatarsal fracture in a patient on long term bisphosphonate therapy. Indian J Orthop 2012;46:589-92. Crossref

5. Valiollahi B, Salehpour M, Bashari H, Majdi Sh, Mohammadpour M. Atypical metatarsal fracture in a patient on long-term bisphosphonate therapy (case report). J Res Orthopedic Sci 2019;6:25-30. Crossref

A young girl aged 9 years 6 months was admitted to hospital in July 2022 with coronavirus disease 2019 infection and found to have refractory hypokalaemia. She reported good past health and denied taking any supplements or medications. Her nonconsanguineous parents and 4-year-old younger brother were healthy and family history was unremarkable.

Her body weight and height were 35.8 kg at the 75th to 95th percentile and 140 cm at the 75th percentile, respectively. Her body mass index was 18.3 kg/m² at the 75th percentile. Blood pressure was noted to be persistently high up to 152/117 mm Hg (112/73 mm Hg being the 90th percentile for her gender, age and height according to the American Academy of Pediatrics1). Cardiovascular and abdominal examinations were unremarkable. There was no hyperpigmentation or sign of virilisation. She was prepubertal, with normal female external genitalia.

Ambulatory blood pressure monitoring confirmed stage 2 hypertension. Electrolytes and hormone profile are summarised in the Table. Her bone age was 8 years 10 months according to the Greulich and Pyle method of assessment. A standard-dose Synacthen test did not stimulate a rise in 17-hydroxyprogesterone or cortisol level. Ultrasound of the pelvis revealed prepubertal uterus and bilateral ovaries. Her karyotype was 46,XX.

Urine steroid profile showed a characteristic pattern compatible with 17-alpha-hydroxylase/17,20-lyase deficiency (17OHD), with a lack of androgen metabolites and an excess of progesterone, pregnenolone, and corticosterone metabolites (online supplementary Appendix).

Oral hydrocortisone was commenced at 7.6 mg/m²/day. Blood pressure improved to 119/81 mm Hg after 2 weeks. Spironolactone was added for better control.

Genetic analysis revealed compound heterozygous pathogenic variants in the CYP17A1 gene: c.297+2T>C in intron 1 and c.849delC p.(Ser284Glnfs*13) in exon 5, which confirmed the diagnosis of 17OHD. Parental testing confirmed that the two CYP17A1 variants were in trans, and the younger brother was a carrier.

17-alpha-hydroxylase/17,20-lyase deficiency is a rare type of congenital adrenal hyperplasia that accounts for 1% of cases with an estimated incidence of 1 in 50 000 to 100 000.2 17-alpha-hydroxylase and 17,20-lyase enzyme defects result in cortisol and sex hormone deficiency, with compensatory rise in adrenocorticotropic hormone that drives excessive production of 11-deoxycorticosterone and corticosterone (Fig).3

Unlike the pathophysiology of the more common types of congenital adrenal hyperplasia such as 21-hydroxylase deficiency and 11-beta-hydroxylase deficiency, 17OHD does not cause excessive testosterone production with consequent virilisation in affected 46,XX females or precocious puberty in both sexes.3 Instead, due to the lack of sex steroid hormone production, it results in undervirilisation in 46,XY males and sexual infantilism in 46,XX females.3 The excessive accumulation of deoxycorticosterone and corticosterone exerts potent mineralocorticoid effects, resulting in sodium and fluid retention, hence suppression of renin with hypokalaemic hypertension,2 as in our patient. A high concentration of corticosterone provides sufficient glucocorticoid effect to prevent adrenal crisis.3 The classic presentation of 17OHD is a phenotypic female with delayed puberty, primary amenorrhoea, and hypokalaemic hypertension with diagnosis often made in young adulthood.2 4 5 Cases of retained partial enzyme activity resulting in ambiguous genitalia in 46,XY males have been reported.3 4

Delayed diagnosis of 17OHD is not uncommon due to its subtle and late presentation. Hypokalaemic hypertension should prompt a clinician to search for secondary causes of hypertension. Plasma renin activity is an important investigation to differentiate the causes, and would be suppressed in 17OHD by the potent mineralocorticoid activity, and is high in renovascular disease.6 On the contrary, aldosterone level could be suppressed, normal or raised in 17OHD.2 4 5 Low aldosterone level arises as a result of a suppressed renin angiotensin system while high level might be related to more severe enzyme defects resulting in greater production of end product from aldosterone precursors.4 As 17OHD has a characteristic pattern of metabolite excretion and metabolite ratios on urine steroid profiling, this profiling is an important investigation when diagnosing the condition.

There is no consensus guideline on the management of 17OHD. The mainstay of treatment is glucocorticoid and sex hormone replacement. The use of glucocorticoid would decrease the adrenocorticotropic hormone drive and production of deoxycorticosterone and corticosterone, which would facilitate improved blood pressure control and electrolyte balance.2 Different forms and dosages of glucocorticoid replacement have been described in the literature, ranging from dexamethasone 0.25 mg to 1 mg daily, or equivalent.2 4 5 In some cases, an antihypertensive agent with a mineralocorticoid antagonist effect such as spironolactone or eplerenone may be required for blood pressure control.3 5 Patients may develop end organ damage such as hypertensive retinopathy if blood pressure control is suboptimal.2 Deoxycorticosterone and corticosterone levels might not be normalised despite treatment. Blood pressure control, electrolyte balance, and renin level are more important markers of disease control.4

Our patient was phenotypically female, in line with her genotypic sex. Her hormone blood test revealed hypergonadotropic hypogonadism due to lack of sex hormone production. Oestrogen and progestin replacement should be commenced at an appropriate time during adolescence, or upon diagnosis in adulthood, to induce secondary sexual characteristics and cyclic uterine bleeding.5 Sex steroid replacement therapy may improve bone mineral density in 17OHD patients and prevent osteoporosis. For genotypic males, psychological assessment should determine gender preference prior to initiation of sex hormone replacement, and intraabdominal testes should be removed to prevent malignant change.3 A multidisciplinary team approach involving an endocrinologist, surgeon, psychiatrist, psychologist and social worker is essential and can help in parental counselling, achieving family consensus for gender assignment, and formulation of an individualised plan for each patient.

Genetic test on CYP17A1 is important to make the diagnosis of 17OHD. To date, the Human Gene Mutation Database has reported >100 different types of mutations on the CYP17A1 gene.7 Genetic analysis showed compound heterozygous pathogenic variants in the CYP17A1 gene (reference transcript: NM_000102.4): c.297+2T>C in intron 1 and c.849delC p.(Ser284Glnfs*13) in exon 5. c.297+2T>C is a splice site variant that has been previously described in patients with 17OHD (ClinVar accession No.: VCV0004319808), while c.849delC is a truncating variant that creates a premature termination codon. It is expected to result in an absent or disrupted protein product (ClinVar accession No.: VCV0014174348). This variant has an extremely low minor allele frequency in the general population and has not been reported in patients with CYP17A1-related disease.

17-alpha-hydroxylase/17,20-lyase deficiency is associated with infertility due to premature follicular arrest and poor endometrial development for implantation.9 Women with 17OHD have difficulty conceiving, even with the help of assisted reproductive technology.9 Though not promising, fertility had been possible for patients with partial 17OHD. Patients should be counselled about potential fertility difficulties and referred to an assisted reproductive service when appropriate.

To conclude, 17OHD should be considered in a young hypertensive individual with hypokalaemia. Timely management with glucocorticoid and sex hormone replacement can ameliorate the morbidity of hypertension and hypogonadism. Multidisciplinary collaboration is advised, especially for patients with gender identification or infertility issues.

All authors contributed to the concept or design, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patient was treated in accordance with the Declaration of Helsinki. The parents of the patient provided written consent for publication of this case report.

The supplementary material was provided by the authors and some information may not have been peer reviewed. Accepted supplementary material will be published as submitted by the authors, without any editing or formatting. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by the Hong Kong Academy of Medicine or the Hong Kong Medical Association. The Hong Kong Academy of Medicine and the Hong Kong Medical Association disclaim all liability and responsibility arising from any reliance placed on the content.

1. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 2017;140:e20171904. Crossref

2. Kim SM, Rhee JH. A case of 17 alpha-hydroxylase deficiency. Clin Exp Reprod Med 2015;42:72-6. Crossref

3. Auchus RJ. Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. J Steroid Biochem Mol Biol 2017;165(Pt A):71-8. Crossref

4. Peter M, Sippell WG, Wernze H. Diagnosis and treatment of 17-hydroxylase deficiency. J Steroid Biochem Mol Biol 1993;45:107-16. Crossref

5. Han LH, Wang L, Wu XY. 17 alpha-hydroxylase deficiency: a case report of young Chinese woman with a rare gene mutation. Clin Case Rep 2022;10:e6109. Crossref

6. Choi KB. Hypertensive hypokalemic disorders. Electrolytes Blood Press 2007;5:34-41. Crossref

7. Institute of Medical Genetics in Cardiff. Human Gene Mutation Database. Available from: https://www.hgmd.cf.ac.uk/ac/index.php. Accessed 24 May 2024.

8. National Center for Biotechnology Information, National Library of Medicine. ClinVar. Available from: https://www.ncbi.nlm.nih.gov/clinvar/". Accessed 24 May 2024.

9. Marsh CA, Auchus RJ. Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase/17,20-lyase deficiency and isolated 17,20-lyase deficiency. Fertil Steril 2014;101:317-22.Crossref

A 60-year-old woman presented to United Christian Hospital in 2019 with a 2-month history of progressive generalised ascending weakness and numbness affecting all four limbs. On clinical examination, she had significant oedema involving her hands and feet. Proximal limb power was full while distal limb power was rated grade 3 on the Medical Research Council scale. Sensory modalities involving pinprick, light touch and proprioception were all diminished distally. She had generalised areflexia. Nerve conduction study revealed markedly reduced motor conduction velocity at 18 to 28 m/s (normal range, >50) in the upper limbs, consistent with demyelination. There was evidence of secondary axonal injury. Limited by significant oedema, lower limb nerve compound muscle action potential and sensory nerve action potential were unrecordable. Cerebrospinal fluid study showed elevated protein level at 899 mg/L with normal white blood cell count. The patient was managed as presumed chronic inflammatory demyelinating polyneuropathy (CIDP). Evaluation of monoclonal gammopathy with serum protein electrophoresis (SPE), urine Bence Jones protein and serum immunoglobulin pattern was unrevealing. Systemic steroid was commenced followed by intravenous immunoglobulin due to disease progression but the patient deteriorated further with distal power grade 0 and became wheelchair bound.

Repeated SPE and urine Bence Jones protein test failed to detect any monoclonal gammopathy. Serum free light chain assay of the patient showed persistently raised lambda light chain but normal kappa/lambda ratio. Serum immunofixation was negative. Six months after her initial presentation, positron emission tomography–computed tomography (PET-CT) scan revealed multiple hypermetabolic bony lesions in the skeleton. The dominant lesions were mixed lytic-sclerotic lesions at the left sacrum (maximum standardised uptake value=22.4) and left L5 vertebra (maximum standardised uptake value=16.3). Mild inactive bilateral pleural effusion, pericardial effusion as well as diffuse subcutaneous oedema were also noted. Random trephine bone marrow examination performed at the right iliac crest was unremarkable.

At this juncture, the patient developed skin changes with plethora, white nails, flushing, and hypertrichosis of the trunk and limbs (Fig). She was oedematous with orthopnoea and paroxysmal nocturnal dyspnoea. A diagnosis of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) was strongly suspected in view of her polyneuropathy, skin changes, lytic-sclerotic bone lesion, and extracellular volume overload. Plasma vascular endothelial growth factor was checked and was markedly elevated at 370 pg/mL (reference range, <96.2).

The patient’s fluid overload symptoms deteriorated with respiratory distress. She was oxygen dependent and diuretic therapy was only partially helpful. Therapeutic thoracentesis of the left chest drained 700 mL of transudative fluid. She subsequently underwent CT-guided bone biopsy (Fig). Her sacrum bone biopsy revealed plasmacytoma with lambda light chain restriction. A diagnosis of POEMS was confirmed.

Around the same time, DNA from the previous random bone marrow blood was extracted from the patient for immunoglobulin heavy chain and kappa light chain B-cell clonality assay (BIOMED-2 polymerase chain reaction assay). Results revealed clonal gene rearrangement (targeting Vk-Jk segments of immunoglobulin kappa gene) consistent with the presence of a clonal B-cell population.

The patient was prescribed a combination of bortezomib, cyclophosphamide and corticosteroid. Oedema resolved first with subsequent improved limb power and dexterity. Her follow-up PET-CT scan after 10 months showed similar bony lesions with reduced metabolic activity.

A 40-year-old man presented to Queen Elizabeth Hospital in 2013 with progressive generalised oedema. He had had repeated admissions for bilateral lower limb oedema, dyspnoea and orthopnoea. Diuretics were partially helpful. Echocardiogram showed normal left ventricular ejection fraction but evidence of pulmonary hypertension. Serum and urine albumin level was normal. Computed tomography of the thorax and abdomen revealed bilateral pleural effusion, pericardial effusion and ascites. He subsequently developed severe distal limb weakness and became wheelchair bound. Nerve conduction study showed demyelinating sensorimotor polyneuropathy in his upper limbs. Lower limb nerves were unable to be assessed due to severe oedema. The patient developed other features of POEMS with hepatosplenomegaly, papilledema, skin changes with hypertrichosis and acrocyanosis. A PET-CT scan revealed sclerotic bony lesions over the left ilium and multiple thoracic and lumbar vertebral bodies.

Similar to Case 1, the patient’s serum and urine were negative for paraprotein. Serum free light chain assay revealed an unremarkable kappa/lambda ratio. Random bone marrow aspiration and trephine biopsy revealed active marrow with mild plasmacytosis. Targeted left iliac bone biopsy showed plasmacytic infiltrates with reversed kappa/lambda ratio. Although plasmacytoma was a concern, there were no definitive histological criteria. Nonetheless based on the highly compatible clinical features of POEMS, he was managed accordingly with cyclophosphamide and corticosteroid. His oedema resolved and he was subsequently able to mobilise with a stick.

The POEMS is a rare paraneoplastic syndrome caused by plasma cell disorder. Presentation may mimic that of demyelinating polyneuropathy. The diagnostic criteria of POEMS include two mandatory criteria, namely, presence of monoclonal plasma cell disorder of lambda origin and demyelinating polyneuropathy. Major criteria include sclerotic bone lesions, elevated vascular endothelial growth factor, and Castleman disease; minor criteria include skin changes, organomegaly, endocrinopathy, extravascular volume overload, papilledema, thrombocytosis, and polycythemia.1 The diagnosis of POEMS is often delayed. The median time for diagnosis has been reported to be 15 months in a longitudinal cohort of 100 patients, by which time 35% patients had become bed or wheelchair bound.2

The above two cases illustrate the difficulty in establishing monoclonal gammopathy even though neurologists and haematologists were alert to the possibility of POEMS. Repeated SPE test, Bence Jones protein test and random bone biopsy were all negative. Plasmacytoma can be demonstrated only on targeted bone biopsy. As a mandatory diagnostic criterion, failure to detect monoclonal gammopathy delays the subsequent management of POEMS. In a large retrospective series, positive monoclonal protein detection on SPE was only 24% to 54%.1

Thorough investigations with serum, urine and histological samples are essential. These consist of performing serum protein electrophoresis, immunofixation, serum free light chain assay as well as urine equivalents. Failure to perform immunofixation and serum free light chain analysis may result in missing 30% of POEMS cases.3 Haematological advice and laboratory communication is of utmost importance to exhaust diagnostic means. For Case 1, immunofixation was performed after liaison with the laboratory. A similar situation arises in the United Kingdom where it is a common practice for laboratories to perform immunofixation only if a paraprotein is present in SPE, despite having superior sensitivity.4

Non-targeted bone marrow examination carries a high chance of missing the pathology, reflected by a prior case series of six patients in whom three had their pathology missed.5 Image guidance, eg, PET-CT, should be considered in the diagnostic workflow of POEMS. It plays a significant role not only in detecting abnormal bone lesions, but also in increasing diagnostic yield for plasmacytoma in biopsy.

Case 1 also illustrates the diagnostic delay of POEMS syndrome partly due to a trial of CIDP treatment, a not uncommon phenomenon. This issue was addressed in a cost-effective analysis of POEMS patients in the United Kingdom.4 The study introduced a diagnostic algorithm incorporating early mandatory vascular endothelial growth factor testing in acquired demyelinating neuropathy patients and helped avoid misdiagnosis and associated healthcare costs.4

The two cases are also similar in terms of the debilitation from significant oedema. One should be alert of POEMS when a CIDP patient presents with unexplained oedema. Extravascular volume overload is a common feature of POEMS and can occur in 90% patients, presumably due to a capillary leak phenomenon.1 This includes leg oedema, pleural effusion, pericardial effusion, ascites, papilledema, and asymptomatic pachymeningeal thickening from fluid collection. Presence of oedema in POEMS should not be overlooked as it is a helpful diagnostic clue to differentiate POEMS from CIDP. It also causes significant patient morbidity. Patients may require repeated paracentesis if the oedema remains refractory to diuretics.

These two cases illustrate the challenge of establishing monoclonal gammopathy in POEMS. Negative serum and urine paraprotein, immunofixation, serum free light chain assay, or a normal random bone marrow examination do not exclude POEMS and warrant further investigations. We should be aware of the limitation of test methods. Comprehensive clinical assessment, thorough investigations and multidisciplinary communication are essential for early diagnosis and management.

Concept or design: YN Mew, WC Fong.
Acquisition of data: All authors.
Analysis or interpretation of data: All authors.
Drafting of the manuscript: YN Mew.
Critical revision of the manuscript for important intellectual content: WC Fong, KF Hui.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

The authors thank Dr Kwan-hung Leung, haematologist at United Christian Hospital, for contributing to patient management.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The patients were managed in accordance with the Declaration of Helsinki and provided informed consent for publication.

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3. Keddie S, D’Sa S, Foldes D, Carr AS, Reilly MM, Lunn MP. POEMS neuropathy: optimising diagnosis and management. Pract Neurol 2018;18:278-90. Crossref

4. Marsh ES, Keddie S, Terris-Prestholt F, D’Sa S, Lunn MP. Early VEGF testing in inflammatory neuropathy avoids POEMS syndrome misdiagnosis and associated costs. J Neurol Neurosurg Psychiatry 2021;92:172-6. Crossref

5. Li Y, Valent J, Soltanzadeh P, Thakore N, Katirji B. Diagnostic challenges in POEMS syndrome presenting with polyneuropathy: a case series. J Neurol Sci 2017;378:170-4. Crossref