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Open access

Marina Yukina, Nurana Nuralieva, Ekaterina Sorkina, Ekaterina Troshina, Anatoly Tiulpakov, Zhanna Belaya, and Galina Melnichenko

Summary

Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS.

Learning points

  • Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood.
  • The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation.
  • The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30.
  • The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible.
  • Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.
Open access

Katsuo Tao, Midori Awazu, Misa Honda, Hironori Shibata, Takayasu Mori, Shinichi Uchida, Tomonobu Hasegawa, and Tomohiro Ishii

Summary

We report a male infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypercalcemia and hyperphosphatemia since birth. Serum sodium started to increase at 39 days. Although there was no polyuria, urine osmolality was 71 mOsm/kg, when serum osmolality was 296 mOsm/kg with plasma arginine vasopressin 22.5 pg/mL. He was thus diagnosed as NDI. An undetectable level of urine calcium and unsuppressed intact parathyroid hormone suggested hyperparathyroidism including calcium-sensing receptor mutations that could cause hypercalcemia-induced NDI. Polyuria became apparent after the initiation of i.v. infusion for the treatment of hypernatremia. Low calcium and low sodium formula with hypotonic fluid infusion did not correct hypernatremia, hypercalcemia, or hyperphosphatemia. Hydrochlorothiazide and subsequently added celecoxib effectively decreased urine output and corrected electrolytes abnormalities. Normal serum electrolytes were maintained after the discontinuation of low calcium formula. The genetic analysis revealed a large deletion of the arginine vasopressin receptor-2 (AVPR2) gene but no pathogenic variant in the calcium-sensing receptor (CASR) gene. Whether hypercalcemia and hyperphosphatemia were caused by dehydration alone or in combination with other mechanisms remains to be clarified.

Learning points

  • Congenital NDI can present with neonatal hypercalcemia and hyperphosphatemia.
  • Hypercalcemia and hyperphosphatemia can be treated with low calcium and low sodium formula, hydration, hydrochlorothiazide, and celecoxib.
  • Genetic testing is sometimes necessary in the differentiating diagnosis of hypercalcemia associated with NDI.
Open access

Tetsuji Wakabayashi, Akihito Takei, Nobukazu Okada, Miki Shinohara, Manabu Takahashi, Shuichi Nagashima, Kenta Okada, Ken Ebihara, and Shun Ishibashi

Summary

The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells.

Learning points

  • Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development.
  • SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome.
  • Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.
Open access

Isaac T Bernhardt, Alistair J Gunn, and Philippa J Carter

Summary

NSD1 deletions are associated with the Sotos syndrome, a syndrome of overgrowth in childhood without evidence of endocrine disturbance. Duplications involving the NSD1 gene have been reported to be associated with a ‘reverse Sotos syndrome’ phenotype, characterised by short stature, microcephaly, dysmorphic features and developmental delay. A 2-year-old girl with short stature, dysmorphic features and developmental delay was found to have duplication of 5q32.2–5q32.3, which includes the NSD1 gene. Growth hormone stimulation testing was normal. Growth hormone therapy was initiated at 5 years of age due to severe short stature and growth failure, with height 3.35 standard deviations (SDS) below the median. Growth velocity increased markedly, by +4.91 SDS in the first year of treatment. At the time of last follow-up at 9 years and 11 months, she had achieved a height within 1 SDS of the median. This is the first report of growth hormone therapy for the short stature associated with duplication of the NSD1 gene, showing that despite normal pituitary function, exogenous growth hormone can dramatically improve linear growth.

Learning points:

  • Sotos syndrome is a disorder of childhood overgrowth caused by NSD1 deletions.
  • Duplications involving NSD1 cause a ‘reverse Sotos syndrome’ phenotype characterised by short stature and microcephaly.
  • The contrasting phenotypes of NSD1 deletions and duplications suggest a dose effect.
  • Stimulated growth hormone secretion is normal in children with NSD1 deletions and duplications.
  • Growth hormone therapy can be very effective in children with NSD1 duplications, comparable to the response seen in severe growth hormone deficiency.
Open access

Alicja Szwilling, Katarzyna Dzygalo, and Jędrzej Nowaczyk

Summary

Kearns–Sayre syndrome (KSS) is a multi-system mitochondrial disease with wide clinical presentation. We describe the case of a 16-year-old girl with KSS accompanied by insulin-dependent diabetes, eosinophilic esophagitis (EoE), Fanconi syndrome, insufficiency of parathyroid gland and severe nutritional problems. Based on recent knowledge, ketogenic diet was introduced to improve metabolic and neurological condition, however in our patient we observed its bad consequences. Unresolved nutritional disorders forced us to proceed with esophagogastroduodenoscopy which revealed EoE. PEG procedure was performed and elemental diet with PPI’s was introduced leading to general improvement in the patient’s health condition.

Learning points:

  • Nutrition is an important factor in supportive care of patients with KSS.
  • Ketogenic diet in patients affected by mitochondrial diseases and diabetes requires careful selection and monitoring.
  • To the best of our knowledge, this is the first case that shows the coexistence of EoE, insulin-dependent diabetes and KSS.
Open access

Sarah W Y Poon, Karen K Y Leung, and Joanna Y L Tung

Summary

Severe hypertriglyceridemia is an endocrine emergency and is associated with acute pancreatitis and hyperviscosity syndrome. We describe an infant with lipoprotein lipase deficiency with severe hypertriglyceridemia who presented with acute pancreatitis. She was managed acutely with fasting and intravenous insulin infusion, followed by low-fat diet with no pharmacological agent. Subsequent follow-up until the age of 5 years showed satisfactory lipid profile and she has normal growth and development.

Learning points:

  • Hypertriglyceridemia-induced acute pancreatitis has significant morbidity and mortality, and prompt treatment is imperative.
  • When no secondary causes are readily identified, genetic evaluation should be pursued in hypertriglyceridemia in children.
  • Intravenous insulin is a safe and effective acute treatment for hypertriglyceridemia in children, even in infants.
  • Long-term management with dietary modifications alone could be effective for primary hypertriglyceridemia due to lipoprotein lipase deficiency, at least in early childhood phase.
Open access

Yang Timothy Du, Lynette Moore, Nicola K Poplawski, and Sunita M C De Sousa

Summary

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology.

Learning points:

  • Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history.
  • Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management.
  • Identification of a genetic disorder may have important implications for family planning.
Open access

Saurabh Uppal, James Blackburn, Mohammed Didi, Rajeev Shukla, James Hayden, and Senthil Senniappan

Summary

Beckwith–Wiedemann syndrome (BWS) can be associated with embryonal tumours and congenital hyperinsulinism (CHI). We present an infant with BWS who developed congenital hepatoblastoma and Wilms’ tumour during infancy. The infant presented with recurrent hypoglycaemia requiring high intravenous glucose infusion and was biochemically confirmed to have CHI. He was resistant to diazoxide but responded well to octreotide and was switched to Lanreotide at 1 year of age. Genetic analysis for mutations of ABCC8 and KCNJ11 were negative. He had clinical features suggestive of BWS. Methylation-sensitive multiplex ligation-dependent probe amplification revealed hypomethylation at KCNQ1OT1:TSS-DMR and hypermethylation at H19 /IGF2:IG-DMR consistent with mosaic UPD(11p15). Hepatoblastoma was detected on day 4 of life, which was resistant to chemotherapy, requiring surgical resection. He developed Wilms’ tumour at 3 months of age, which also showed poor response to induction chemotherapy with vincristine and actinomycin D. Surgical resection of Wilms’ tumour was followed by post-operative chemotherapy intensified with cycles containing cyclophosphamide, doxorubicin, carboplatin and etoposide, in addition to receiving flank radiotherapy. We report, for the first time, an uncommon association of hepatoblastoma and Wilms’ tumour in BWS in early infancy. Early onset tumours may show resistance to chemotherapy. UPD(11p15) is likely associated with persistent CHI in BWS.

Learning points:

  • Long-acting somatostatin analogues are effective in managing persistent CHI in BWS.
  • UPD(11)pat genotype may be a pointer to persistent and severe CHI.
  • Hepatoblastoma and Wilms’ tumour may have an onset within early infancy and early tumour surveillance is essential.
  • Tumours associated with earlier onset may be resistant to recognised first-line chemotherapy.
Open access

Priya Vaidyanathan and Paul Kaplowitz

Summary

Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1–2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene.

Learning points:

  • Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization.
  • The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS.
  • Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.
Open access

Benjamin Kwan, Bernard Champion, Steven Boyages, Craig F Munns, Roderick Clifton-Bligh, Catherine Luxford, and Bronwyn Crawford

Summary

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members.

Learning points:

  • ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.
  • In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.
  • CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.
  • Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.