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Open access

Pranav Gupta, Karen Loechner, Briana C Patterson, and Eric Felner

Summary

Insulinomas are a rare cause of persistent hypoglycemia in a previously healthy child. In addition to symptoms of hypoglycemia, individuals with insulinomas usually present with a history of incessant caloric intake and weight gain due to a constant need to counter hypoglycemia. In addition to an extensive review of the literature, we report the first case of an insulinoma coexisting with reduced appetite secondary to anorexia nervosa in an adolescent female.

Learning points

  • Eliciting a detailed family history is important in hypoglycemia cases.

  • Obtaining a thorough dietary intake, weight history, and menstrual cycles (in females) and considering a psychiatric consultation for an eating disorder when indicated.

  • Although rare in the pediatric population, multiple endocrine neoplasia type 1 syndrome should be considered in the evaluation of children and adolescents with hypoglycemia who also have a family history of pituitary, pancreatic, and/or parathyroid endocrinopathies.

Open access

Priya Darshani Chhiba and David Segal

Summary

Recombinant human growth hormone therapy (rhGH) has been available since 1985 for a variety of conditions and has expanded the indications for rhGH therapy and the number of patients receiving therapy. The very nature of the therapy exposes individuals to years of injections. There are a number of well-known adverse events, however, a lesser-known and rarely reported adverse event of rhGH therapy is localized lipoatrophy. We report nine cases of localized lipoatrophy during rhGH therapy accounting for 14.5% of patients taking rhGH presenting to a single centre for routine follow-up over just a 2-month period. The development of localized lipoatrophy does not appear to be age, indication or dose-related but rather related to repeated administration of rhGH into a limited number of sites. The most likely putative mechanism is the local lipolytic action of growth hormone (GH) itself, although the possibility of an excipient-based interaction cannot be excluded. Given the high prevalence of this adverse event and the potential to prevent it with adequate site rotation, we can recommend that patients be informed of the possible development of localized lipoatrophy. Doctors and nurses should closely examine injection sites at each visit, and site rotation should be emphasized during injection technique education.

Learning points

  • There are a number of well-known adverse events, however, a lesser-known and rarely reported adverse event of rhGH therapy is localized lipoatrophy.

  • Examination of the injection sites at each visit by the treating healthcare practitioner.

  • To advise the parents/caregivers/patients to change their injection site with each injection.

  • To advise the parents/caregivers/patients to change the needles after every use.

  • For parents, caregivers and patients to self-inspect their injection sites and have a high alert for the development of lipoatrophy and to then immediately report it to their doctor.

Open access

Angelika Mohn, Nella Polidori, Chiara Aiello, Cristiano Rizzo, Cosimo Giannini, Francesco Chiarelli, and Marco Cappa

Summary

Adrenoleukodystrophy is a peroxisomal X-linked recessive disease caused by mutations in the ABCD1 gene, located on the X-chromosome (Xq28). Gene mutations in patient with adrenoleukodystrophy induce metabolic alterations characterized by impaired peroxisomal beta-oxidation and accumulation of very long chain fatty acid (VLCFA) in plasma and in all tissues. Although nutritional intervention associated with a various mixture of oil prevents the accumulation of VLCFA, to date no causal treatment is available. Therefore, haematopoietic stem cell transplantation (HSCT) and gene therapy are allowed only for very early stages of cerebral forms diagnosed during childhood.We reported a case series describing five family members affected by X-linked adrenoleukodystrophy caused by a novel mutation of the ABCD1 gene. Particularly, three brothers were affected while the sister and mother carried the mutation of the ABCD1 gene. In this family, the disease was diagnosed at different ages and with different clinical pictures highlighting the wide range of phenotypes related to this novel mutation. In addition, these characteristics stress the relevant role of early diagnosis to properly set a patient-based follow-up.

Learning points

  • We report a novel mutation in the ABCD1 gene documented in a family group associated to an X-ALD possible Addison only phenotype.

  • All patients present just Addison disease but with different phenotypes despite the presence of the same mutations. Further follow-up is necessary to complete discuss the clinical development.

  • The diagnosis of ALD needs to be included in the differential diagnosis in all patients with idiopathic PAI through accurate evaluation of VLCFA concentrations and genetic confirmation testing.

  • Early diagnosis of neurological manifestation is important in order to refer timely to HSCT.

  • Further follow-up of these family members is necessary to characterize the final phenotype associated with this new mutation.

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

Carolina Chaves, Mariana Chaves, João Anselmo, and Rui César

Summary

Berardinelli–Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disease, characterized by the absence of subcutaneous adipose tissue, leptin deficiency and severe metabolic complications, such as insulin resistance, diabetes mellitus, and dyslipidemia. The most common mutation occurs in BCSL2 which encodes seipin, a protein involved in adipogenesis. We report a patient with BSCL who was diagnosed with diabetes at 11 years old. He was started on metformin 1000 mg twice daily, which lowered glycated hemoglobin (HbA1c) to less than 7%. Four months later, HbA1c raised above 7.5%, indicating secondary failure to metformin. Therefore, we added the peroxisome proliferator-activated receptor-gamma (PPARG) agonist, pioglitazone. Since then and for the last 5 years his HbA1c has been within the normal range. These findings indicate that pioglitazone should be considered as a valid alternative in the treatment of diabetes in BSCL patients. To the best of our knowledge, this is the first specific report of successful long-term treatment with pioglitazone in a patient with BSCL.

Learning points

  • Berardinelli–Seip congenital lipodystrophy (BSCL) is a recessive genetic disorder associated with severe insulin resistance and early onset diabetes, usually around puberty. Failure of oral antidiabetic medication occurs within the first years of treatment in BSCL patients.

  • When failure to achieve metabolic control with metformin occurs, pioglitazone may be a safe option, lowering insulin resistance and improving both the metabolic control and lipodystrophic phenotype.

  • Herein we show that pioglitazone can be a safe and efficient alternative in the long-term treatment of BSCL patients with diabetes.

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

Shunsuke Shimazaki, Itsuro Kazukawa, Kyoko Mori, Makiko Kihara, and Masanori Minagawa

Summary

Ammonium acid urate (AAU) crystals are rare in industrialized countries. Furthermore, the number of children with diabetic ketoacidosis (DKA) who develop severe acute kidney injury (AKI) after hospitalization is small. We encountered two patients with AKI caused by AAU crystals during the recovery phase of DKA upon admission. They were diagnosed with severe DKA and hyperuricemia. Their urine volume decreased and AKI developed several days after hospitalization; however, acidosis improved in both patients. Urine sediment analysis revealed AAU crystals. They were treated with urine alkalization and diuretics. Excretion of ammonia in the urine and urine pH levels increased after treatment of DKA, which resulted in the formation of AAU crystals. In patients with severe DKA, the urine and urine sediment should be carefully examined as AAU can form in the recovery phase of DKA.

Learning points:

  • Ammonium acid urate crystals could be formed in the recovery phase of diabetic ketoacidosis.

  • Diabetic ketoacidosis patients may develop acute kidney injury caused by ammonium acid urate crystals.

  • Urine and urine sediment should be carefully checked in patients with severe DKA who present with hyperuricemia and volume depletion.

Open access

Nami Mohammadian Khonsari, Benyamin Hakak-Zargar, Tessa Voth, and Shahab Noorian

Summary

Multiple sulfatase deficiency (MSD) is a lysosomal storage disorder (LSD) that results in the accumulation of sulfate esters which go on to cause neurological deterioration and mental delay, skin changes, and dysmorphism. The disease can be categorized into three subtypes based on the age of onset: neonatal, late infantile, or juvenile. Our patient is a 2.5-year-old girl, the only child of a healthy couple. Prior to the presentation of the disease, she had not been noted to have any previous health complications. The condition began at the age of 6 months with developmental regression and global hypotonia. Following thorough evaluation and testing, the patient was diagnosed with severe late infantile MSD, although some features, such as minimal mental deterioration, minimal dysmorphic facial features, and minimal organ enlargement, did not fully correlate with the diagnosis, since in cases of severe forms of the condition these features are almost always quite marked. The unexpected minimalism of some of the patient’s MSD signs in spite of the severity of her MSD condition made her case worth further studying.

Learning points:

  • Treating dermatologic signs and symptoms greatly eased our patient’s discomfort.

  • We would suggest the use of appropriate supportive treatment for symptom management regardless of the life expectancy of the patient.

  • As regards the diagnosis of MLD, given that in some cases the patient may present with irregular features of the condition, a genetic evaluation may be useful for accurate diagnosis.

  • If motor function impairment is followed by dermatologic involvement, as seen in our patient and in many cases in the literature, MSD must be considered, and additional tests should be done to rule it out.