A 54-year-old man was referred to the genetic clinic with familial nail dysplasia in September 2012 (Fig 1). On further questioning, he reported recurrent knee pain due to patellar dislocation. There was no elbow involvement or renal problem. A skeletal survey was performed in view of his skeletal complaint (Fig 2). His family history was significant: his paternal grandfather, father, and two of his paternal uncles also had nail dysplasia and knee problems, but had undergone no formal medical assessment. What is the diagnosis?

The combination of nail dysplasia, patella hypoplasia, and iliac horn led to the clinical diagnosis of nail-patella syndrome (NPS). This syndrome is also known as Fong disease or hereditary osteo-onychodysplasia. Multiple organ systems are affected including the nails, the eyes, the kidneys, and the skeleton. The clinical presentation of NPS can be highly heterogeneous and is summarised in the Table.1 2 It is a rare autosomal dominant disease with a prevalence of about 1 in 50 000 newborn.1 It is highly penetrant but with significant intra- and inter-familial variability in expression.

The diagnosis of NPS is usually based on clinical findings. It is straightforward when the classic tetrad of abnormal nails, elbows, knees, and iliac horns are present. Nonetheless molecular genetic testing should be considered when the diagnosis is in doubt, or when prenatal or pre-implantation diagnosis is desired. The LMX1B gene is the only gene known to be associated with NPS. Sequence analysis would identify the LMX1B gene mutation in 85% of cases of NPS.

LMX1B gene sequencing was performed for this patient (Fig 3) and revealed a missense mutation LMX1B NM_002316.3}:c.[175T>C];[=];LMX1B{NP _002307.2}:p.[Cys59Arg];[=]. This changed the 59th amino acid from cysteine to arginine in the LIM-A domain of the LMX1B protein. It was located in an evolutionarily highly conserved region and has been reported in the literature to be associated with NPS. Therefore, it was considered to be pathogenic.3

To date, more than 150 mutations of the LMX1B gene have been reported, but no clear genotype-phenotype correlation has been demonstrated. LMX1B has been demonstrated in animal models to be involved in multiple developmental functions including dorso-ventral patterning of the limb bud, and cellular differentiation in the kidney. Nonetheless the exact pathogenesis of NPS has not been elucidated.4

Upon initial diagnosis, comprehensive renal, orthopaedic, and ophthalmological assessments are essential. The renal manifestation strongly affects the long-term prognosis. Kidney involvement occurs in 30% to 50% of patients, but kidney failure only occurs in 3% to 5%.2 Since nephropathy may not develop until later in life, prospective monitoring is essential for all NPS patients. Primary open-angle glaucoma or ocular hypertension occurs in 10% of NPS patients so regular eye surveillance is also warranted. Nail-patella syndrome is an autosomal dominant disorder with a 50% chance of occurrence in offspring, thus genetic counselling is essential (Box2). Genetic testing of other at-risk family members, and prenatal and pre-implantation genetic diagnoses are possible only if the disease-causing mutation is known in the index patient.

1. Bongers EM, Gubler MC, Knoers NV. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 2002;17:703-12. Crossref

2. Sweeney E, Fryer A, Mountford R, Green A, McIntosh I. Nail-patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet 2003;40:153-62. Crossref

3. Clough MV, Hamlington JD, McIntosh I. Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients. Hum Mutat 1999;14:459-65. Crossref

4. Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in LMX1B mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet 1998;19:51-5. Crossref

A 79-year-old man with lymphoma was admitted for chemotherapy in November 2014. During his admission, he complained of acute onset of left eye pain with loss of vision. There was no history of previous eye disease or injury.

On examination, his left eye had no light perception and intra-ocular pressure was raised to more than 50 mm Hg. There was left eye proptosis, chemosis, and oedema over the eyelid. There was no fundal view. B-scan performed by the ophthalmologist showed increased vitreous echogenicity. A complete blood picture showed low levels of haemoglobin (104 g/L) and thrombocytopenia (13 x 10⁹ /L), and total white cell count reduced to 0.69 x 10⁹ /L. Blood was taken from the central line for culture. Computed tomographic scan of the orbit was performed to look for intra-orbital haematoma as the platelet level was low. Computed tomographic scan showed left proptosis, left eyelid swelling, and increased soft tissue stranding in the retro-ocular space (Fig 1). The lens was dislocated into the posterior chamber and the density of vitreous humour was increased when compared with the right globe. The difference in densities between the two globes was exaggerated at a follow-up scan 6 hours later (Fig 2). Overall radiological findings were compatible with severe inflammation of the globe with pus in the posterior chamber complicated by lens dislocation. The patient was diagnosed with endophthalmitis and antibiotic treatment was started. The patient began to have pustular discharge from a ruptured corneal ulcer and subsequent evisceration of the eye was required. The specimen and the initial blood culture were positive for Bacillus species. The organism was sensitive for vancomycin and gentamicin.

Endophthalmitis can be classified broadly into endogenous or exogenous and can cause permanent blindness. Exogenous endophthalmitis is usually due to trauma or postoperative infection. Endogenous endophthalmitis is commonly due to bacteraemia and immunocompromised patients are at particular risk.

Endogenous endophthalmitis is relatively uncommon, accounting for 2% to 8% of all endophthalmitis cases. Staphylococcus aureus, Bacillus cereus, Escherichia coli, Neisseria meningitidis, and Klebsiella are common pathogens.1 Bacillus cereus is a highly virulent organism as it can produce toxins that trigger severe intra-ocular inflammation and can cause complete loss of vision or destruction of the globe within 24 to 48 hours.1 2 Patients may end up with enucleation and permanent loss of vision. Intravenous drug abusers are prone to Bacillus infection.3 The cause of Bacillus infection in our patient was unknown although the central venous catheter was a potential culprit.

This article illustrates the radiological features of endophthalmitis. It is usually a clinical diagnosis although imaging may be required in complicated cases. The prognosis for Bacillus endophthalmitis is poor despite vigorous treatment.

1. Callegan MC, Engelbert M, Parke DW 2nd, Jett BD, Gilmore MS. Bacterial endophthalmitis: epidemiology, therapeutics, and bacterium-host interactions. Clin Microbiol Rev 2002;15:111-24. Crossref

2. Kumar N, Garg N, Kumar N, Van Wagoner N. Bacillus cereus panophthalmitis associated with injection drug use. Int J Infect Dis 2014;26:165-6. Crossref

3. Hatem G, Merritt JC, Cowan CL Jr. Bacillus cereus panophthalmitis after intravenous heroin. Ann Ophthalmol 1979;11:431-40.

The patient was a 40-year-old female with a 5-month history of recurrent painful labial ulcers in December 2013. Investigations by a private physician revealed a negative VDRL (Venereal Disease Research Laboratory) test and vulval swab culture grew commensals only. The ulcers, however, failed to heal following treatment with antibiotics.

Vulval biopsy was performed at her first visit and histopathology report revealed only a non-specific ulcer with negative stains for fungus, bacteria, acid-fast bacilli, and herpes simplex virus. Papanicolaou smear showed atypical squamous cells of unknown significance (ASCUS).

In the absence of any obvious pathology for the non-healing ulcer, colposcopy was arranged: four ulcers were identified within the vagina, scattered over the right and left vaginal walls (Fig 1). A left lower vulval ulcer measuring 3 cm with slightly raised edges was also seen (Fig 2). Biopsies were taken over the cervix, vaginal, and vulval ulcers. Histopathology of these biopsies confirmed the presence of cervicitis and ulcers, with no evidence of malignancy.

Upon systemic review, the patient revealed that she had been suffering from recurrent mouth ulcers and bruising over both shins. Subsequent examination revealed multiple aphthous mouth ulcers, as well as erythema nodosum over both shins.

Based on the clinical signs, a diagnosis of Behçet’s disease was made. The patient was commenced on prednisolone, and all ulcers had healed at subsequent follow-up.

Behçet’s disease is a rare cause of genital ulceration. It is a multisystem vasculitic disorder and the diagnosis is based on clinical criteria.1 2 3 4 Our patient fulfilled the criteria of recurrent oral and genital ulcerations as well as a cutaneous manifestation.

Although there is little published evidence to support the value of colposcopy and biopsy in the diagnosis of Behçet’s disease, colposcopy enables a more detailed evaluation of the genital tract, and can be used to exclude the possibility of malignancy. Histopathological results in Behçet’s ulcer are typically non-specific with chronic active inflammation.

Papanicolaou smear in our patient showed ASCUS, but histopathology result for the cervix was normal. In a prospective study by Özdemir et al,2 abnormal cervical cytology, acetowhite epithelium, and iodine-negative epithelium on colposcopy were more common in Behçet’s patients. Nonetheless, the majority of ASCUS results revealed a normal finding for cervical histopathology. It was suggested that this was due to the benign inflammatory changes in the cervical epithelium.2

As in this case, diagnosis for recurrent genital ulcers can be difficult although when information about oral ulcers became available, a diagnosis of Behçet’s became more obvious. A complete history and physical examination that pays particular attention to signs or symptoms of an underlying associated systemic condition are essential when evaluating patients with recurrent genital ulcers.

1. Patel S, Prime K. Recurrent vulval ulceration: could it be Behçet’s disease? Int J STD AIDS 2012;23:683-4. Crossref

2. Özdemir S, Özdemir M, Celik C, Balevi A, Toy H, Kamış U. Evaluation of patients with Behçet’s disease by cervical cytology and colposcopic examination. Arch Gynecol Obstet 2012;285:1363-8. Crossref

3. Keogan MT. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Clin Exp Immunol 2009;156:1-11. Crossref

4. Bandow GD. Diagnosis and management of vulvar ulcers. Dermatol Clin 2010;28:753-63. Crossref

A 90-year-old Caucasian female was admitted to the hospital following a fall preceded by left thigh pain for 2 weeks in May 2013. Her medical history included postmenopausal osteoporosis, depression, ischaemic heart disease, and atrial fibrillation. She was on alendronate for 11 years, as well as aspirin, bisoprolol, digoxin, calcium, vitamin D, frusemide, metformin, paracetamol, pantoprazole, and sertraline for around 14 years prior to hospital admission.

The Figure shows an atypical diaphyseal fracture of the femur commonly associated with long-term bisphosphonate therapy. These fractures usually occur in patients taking bisphosphonates for more than 5 years although it is known to occur with shorter duration of usage and in bisphosphonate-naïve patients (10%).1 This patient fulfilled all the ASBMR (American Society for Bone and Mineral Research) task force major and minor criteria for atypical fractures.2 The mandatory major criterion is fracture located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. In addition, at least four of five major features must be present: (1) The fracture is associated with minimal or no trauma, as in a fall from a standing height or less. (2) The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may become oblique as it progresses medially across the femur. (3) Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex. (4) The fracture is non-comminuted or minimally comminuted. (5) There is localised periosteal or endosteal thickening of the lateral cortex at the fracture site (“beaking” or “flaring”). The minor features not essential for diagnosis include: generalised increase in cortical thickness of the femoral diaphysis, unilateral or bilateral prodromal symptoms such as dull or aching pain in the groin or thigh, bilateral incomplete or complete femoral diaphysis fracture, and delayed fracture healing. Differential diagnoses in these patients include femoral fractures with subtrochanteric extension, pathological fractures associated with tumours, and periprosthetic fractures.2

Management strategies include cessation of bisphosphonates, protected weight-bearing, prophylactic intramedullary rod insertion, and use of anabolic bone agents like teriparatide or strontium.3 It is unclear whether a drug holiday is useful to prevent these fractures.4 Our patient was treated with intramedullary nailing and commenced on strontium after cessation of bisphosphonates. Greater awareness of this condition would prevent misdiagnosis especially in frail older patients and facilitate proper management.

Dr PK Shibu has received educational grants and honorarium from Novartis Pty Australia for Osteoporosis and Fracture Liaison related clinical research projects or lectures in the past and received honorarium from Amgen Ltd for presenting at educational meetings in the past.

1. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012;27:2544-50. Crossref

2. 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

3. Carvalho NN, Voss LA, Almeida MO, Salgado CL, Bandeira F. Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide. J Clin Endocrinol Metab 2011;96:2675-80. Crossref

4. Diab DL, Watts NB. Bisphosphonate drug holiday: who, when and how long. Ther Adv Musculoskelet Dis 2013;5:107-11. Crossref