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Open access

Jia Xuan Siew and Fabian Yap

Summary

Growth anomaly is a prominent feature in Wolf-Hirschhorn syndrome (WHS), a rare congenital disorder caused by variable deletion of chromosome 4p. While growth charts have been developed for WHS patients 0–4 years of age and growth data available for Japanese WHS patients 0–17 years, information on pubertal growth and final height among WHS children remain lacking. Growth hormone (GH) therapy has been reported in two GH-sufficient children with WHS, allowing for pre-puberty catch up growth; however, pubertal growth and final height information was also unavailable. We describe the complete growth journey of a GH-sufficient girl with WHS from birth until final height (FH), in relation to her mid parental height (MPH) and target range (TR). Her growth trajectory and pubertal changes during childhood, when she was treated with growth hormone (GH) from 3 years 8 months old till 6 months post-menarche at age 11 years was fully detailed.

Learning points:

  • Pubertal growth characteristics and FH information in WHS is lacking.

  • While pre-pubertal growth may be improved by GH, GH therapy may not translate to improvement in FH in WHS patients.

  • Longitudinal growth, puberty and FH data of more WHS patients may improve the understanding of growth in its various phases (infancy/childhood/puberty).

Open access

Pradeep Vasudevan, Corrina Powell, Adeline K Nicholas, Ian Scudamore, James Greening, Soo-Mi Park and Nadia Schoenmakers

Summary

In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.

Learning points:

  • CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.

  • CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.

  • Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.

  • Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

Open access

Durgesh Prasad Chaudhary, Tshristi Rijal, Kunal Kishor Jha and Harpreet Saluja

Summary

Combined pituitary hormonal deficiency (CPHD) is a rare disease that results from mutations in genes coding for transcription factors that regulate the differentiation of pituitary cells. PROP1 gene mutations are one of the etiological diagnoses of congenital panhypopituitarism, however symptoms vary depending on phenotypic expression. We present a case of psychosis in a 36-year-old female with congenital panhypopituitarism who presented with paranoia, flat affect and ideas of reference without a delirious mental state, which resolved with hormone replacement and antipsychotics. Further evaluation revealed that she had a homozygous mutation of PROP1 gene. In summary, compliance with hormonal therapy for patients with hypopituitarism appears to be effective for the prevention and treatment of acute psychosis symptoms.

Learning points:

  • Patients with PROP1 gene mutation may present with psychosis with no impairment in orientation and memory.

  • There is currently inadequate literature on this topic, and further study on the possible mechanisms of psychosis as a result of endocrine disturbance is required.

  • Compliance with hormonal therapy for patients with hypopituitarism appears to be effective for prevention and treatment of acute psychosis symptoms.

Open access

Kharis Burns, Darshika Christie-David and Jenny E Gunton

Summary

Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease.

Learning points

  • Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.

  • Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.

  • Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.

  • Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.

Open access

Shweta Birla, Viveka P Jyotsna, Rajiv Singla, Madhavi Tripathi and Arundhati Sharma

Summary

Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease characterized by tumors in endocrine and/or non endocrine organs due to mutations in MEN1 encoding a nuclear scaffold protein‘menin’ involved in regulation of different cellular activities. We report a novel 14 bp MEN1 deletion mutation in a 35-year-old female with history of recurrent epigastric pain, vomiting, loose stools and weight loss. On evaluation she was diagnosed to have multifocal gastro-duodenal gastrinoma with paraduodenal lymph nodes and solitary liver metastasis. She was also found to have primary hyperparathyroidism with bilateral inferior parathyroid adenoma. Pancreatico-duodenectomy with truncalvagotomy was performed. Four months later, radiofrequency ablation (RFA) of segment 4 of the liver was done followed by three and a half parathyroidectomy. MEN1 screening was carried out for the patient and her family members. MEN-1 sequencing in the patient revealed a heterozygous 14 bp exon 8 deletion. Evaluation for pathogenicity and protein structure prediction showed that the mutation led to a frameshift thereby causing premature termination resulting in a truncated protein. To conclude, a novel pathogenic MEN1 deletion mutation affecting its function was identified in a patient with hyperparathyroidism and gastrinoma. The report highlights the clinical consequences of the novel mutation and its impact on the structure and function of the protein. It also provides evidence for co-existence of pancreatic and duodenal gastrinomas in MEN1 syndrome. MEN1 testing provides important clues regarding etiology and therefore should be essentially undertaken in asymptomatic first degree relatives who could be potential carriers of the disease.

Learning points

  • Identification of a novel pathogenic MEN1 deletion mutation.

  • MEN1 mutation screening in patients with pituitary, parathyroid and pancreatic tumors, and their first degree relatives gives important clues about the etiology.

  • Pancreatic and duodenal gastrinomas may co-exist simultaneously in MEN1 syndrome.

Open access

Soham Mukherjee, Anuradha Aggarwal, Ashu Rastogi, Anil Bhansali, Mahesh Prakash, Kim Vaiphei and Pinaki Dutta

Summary

Spontaneous diabetic muscle infarction (DMI) is a rare and under diagnosed complication of diabetes mellitus. Clinically it presents with acute to subacute onset swelling, pain and tenderness of muscle(s) without systemic manifestations. MRI is helpful in diagnosis, exclusion of other causes and for localization of affected muscle for biopsy in atypical cases. Muscles of the thighs are commonly affected in diabetic myonecrosis (DMN). Here we present the summary of four cases seen in the last 3 years in a tertiary care centre with simultaneous or sequential involvement of multiple groups of muscles or involvement of uncommon sites. All these patients had advanced duration of diabetes with microvascular complications and poor glycemic control. Conservative management including rest and analgesics is the treatment of choice. Short-term prognosis is good but there may be recurrence.

Learning points

  • A high index of suspicion is required for the diagnosis of DMN which can avoid inadvertent use of antibiotics.

  • Acute–subacute onset severe focal muscle pain in the absence of systemic symptoms in a female patient with long-standing diabetes with microvascular complications suggests DMI.

  • MRI is the most sensitive test for diagnosis.

  • Muscle biopsy should be reserved for atypical cases.

  • Conservative management including rest and analgesics has good outcome.

  • Improvement usually occurs within 6–8 weeks, but there may be recurrence.

Open access

Kirun Gunganah, Ashley Grossman and Maralyn Druce

Summary

A 22-year-old female student presented with a history of recurrent pancreatitis. The commonest causes of pancreatitis, including drugs, gallstones, corticosteroids, excess alcohol and hypertriglyceridaemia, were excluded. She was found to have an elevated serum calcium level that was considered to be the cause of her pancreatitis, with a detectable serum parathyroid hormone (PTH). An initial diagnosis of primary hyperparathyroidism was made. However, two neck explorations failed to reveal a parathyroid adenoma. She was referred to our unit three years later as her episodes of pancreatitis were becoming more frequent and her calcium level remained persistently elevated. Her investigations were as follows: elevated adjusted calcium level of 2.79 mmol/l (2.2–2.58), PTH level of 4.2 pmol/l (0.6–6.0), low 24 h urine calcium of 0.3 mmol/l and a urine calcium:creatinine ratio of <0.003. A clinical diagnosis of familial hypocalciuric hypercalcaemia (FHH) was made and confirmed on genetic testing that showed a c.1703 G>A mutation in the calcium-sensing receptor gene. Although the hypercalcaemia of FHH is usually without sequelae due to the generalised changes in calcium sensing, in the presence of this complication she was started on cinacalcet 30 mg daily. She had one further episode of pancreatitis with calcium levels ranging between 2.53 and 2.66 mmol/l. Her cinacalcet was gradually increased to 30 mg three times daily, maintaining her calcium levels in the range of 2.15–2.20 mmol/l. She has not had a further episode of pancreatitis for more than 2 years.

FHH is usually a benign condition with minimal complications from hypercalcaemia. Pancreatitis has been reported rarely, and no clear management strategy has been defined in these cases. Cinacalcet was successfully used in treating recurrent pancreatitis in a patient with FHH by maintaining calcium levels in the lower part of the reference range. Whether or not this is an effective long-term treatment remains yet to be seen.

Learning points

  • FHH is an important differential diagnosis for hypercalcaemia.

  • FHH can rarely cause pancreatitis.

  • No clear strategy is available to help in the management of patients with pancreatitis due to FHH.

  • Cinacalcet was effective in lowering serum calcium levels and reducing the frequency of pancreatitis in our patient with FHH.

Open access

Pinaki Dutta, Anuradha Aggarwal, Yashpal Gogate, Uma Nahar, Viral N Shah, Mandeep Singla, N Khandelwal and Anil Bhansali

Summary

We describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.

Learning points

  • NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.

  • Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.

  • IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

Open access

Pramila Dharmshaktu, Aditya Kutiyal and Dinesh Dhanwal

Summary

A 21-year-old female patient recently diagnosed with severe hypothyroidism was found to have a large ovarian cyst. In view of the large ovarian cyst, she was advised to undergo elective laparotomy in the gynaecology department. She was further evaluated in our medical out-patient department (OPD), and elective surgery was withheld. She was started on thyroxine replacement therapy, and within a period of 4 months, the size of the cyst regressed significantly, thereby improving the condition of the patient significantly. This case report highlights the rare and often missed association between hypothyroidism and ovarian cysts. Although very rare, profound hypothyroidism that can cause ovarian cysts in an adult should always be kept in the differential diagnosis to avoid unnecessary ovarian surgery.

Learning points

  • Hypothyroidism should be considered in the differential diagnosis of adult females presenting with multicystic ovarian tumours.

  • Adequate thyroid hormone replacement therapy can prevent these patients from undergoing unnecessary and catastrophic ovarian resection.

  • Surgical excision should be considered only when adequate thyroid replacement therapy fails to resolve ovarian enlargement.

  • In younger women with ovarian cysts, it is also desirable to avoid unnecessary surgery so as to not compromise fertility in the future.

Open access

Jayshree Swain, Shruti Sharma, Ved Prakash, N K Agrawal and S K Singh

Summary

Ovarian steroid cell tumors are very rare functioning sex-cord stromal tumors. They comprise <0.1% of all ovarian tumors. Previously designated as lipoid cell tumors, one-third of these tumors are considered malignant with the mean age of presentation at around 40 years. We present a case of a 28-year-old female with 2-year history of hirsutism, virilization, and amenorrhea. She was diagnosed with left ovarian tumor, for which she underwent left salpingo-oophorectomy. Histopathology revealed not otherwise specified subtype of steroid cell tumors. The patient resumed menses 2 months after the features of masculinization regressed. Within 1 year of surgery, the patient successfully conceived a full-term baby without any complications. In a young female, the neoplastic etiology of a rapid virilization or menses changing should always be kept in mind. Though commonly observed in adult females, steroid cell tumors have very good surgical outcomes if age at presentation is less and tumor is unilateral, and there are no evidences of bilateral malignancy. Bilateral salpingo-oophorectomy is not required.

Learning points

  • In a case of severe rapid hirsutism and virilization with serum testosterone level more than 200 ng/dl or more than threefold of the normal range, neoplastic conditions should always be suspected.

  • Steroid cell tumor in young women without evidence of malignancy on histopathology has excellent surgical outcomes.

  • Unilateral salpingo-oophorectomy is the surgery of choice.

  • As the frequency of bilateralism is only 6%, prophylactic unaffected side oophorectomy need not be done.