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Open access

Bronwen E Warner, Carol D Inward and Christine P Burren

Summary

This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic–pituitary–gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management.

Learning points:

  • Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.

  • We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.

  • Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.

Open access

Rossella Mazzilli, Michele Delfino, Jlenia Elia, Francesco Benedetti, Laura Alesi, Luciana Chessa and Fernando Mazzilli

Summary

We report the case of a 19-year-old boy, presenting several congenital malformations (facial dysmorphisms, cardiac and musculoskeletal abnormalities), mental retardation, recurrent respiratory infections during growth and delayed puberty. Although previously hospitalised in other medical centres, only psychological support had been recommended for this patient. In our department, genetic, biochemical/hormonal and ultrasound examinations were undertaken. The karyotype was 49,XXXXY, a rare aneuploidy with an incidence of 1/85 000–100 000, characterised by the presence of three extra X chromosomes in phenotypically male subjects. The hormonal/biochemical profile showed hypergonadotropic hypogonadism, insulin resistance and vitamin D deficiency. The patient was then treated with testosterone replacement therapy. After 12 months of treatment, we observed the normalisation of testosterone levels. There was also an increase in pubic hair growth, testicular volume and penis size, weight loss, homeostatic model assessment index reduction and the normalisation of vitamin D values. Moreover, the patient showed greater interaction with the social environment and context.

Learning points

  • In cases of plurimalformative syndrome, cognitive impairment, recurrent infections during growth and, primarily, delayed puberty, it is necessary to ascertain as soon as possible whether the patient is suffering from hypogonadism or metabolic disorders due to genetic causes. In our case, the diagnosis of hypogonadism, and then of 49,XXXXY syndrome, was unfortunately made only at the age of 19 years.

  • The testosterone replacement treatment, even though delayed, induced positive effects on: i) development of the reproductive system, ii) regulation of the metabolic profile and iii) interaction with the social environment and context.

  • However, earlier and timely hormonal replacement treatment could probably have improved the quality of life of this subject and his family.

Open access

Renata Lange, Caoê Von Linsingen, Fernanda Mata, Aline Barbosa Moraes, Mariana Arruda and Leonardo Vieira Neto

Summary

Ring chromosomes (RCs) are uncommon cytogenetic findings, and RC11 has only been described in 19 cases in the literature. Endocrine abnormalities associated with RC11 were reported for two of these cases. The clinical features of RC11 can result from an alteration in the structure of the genetic material, ring instability, mosaicism, and various extents of genetic material loss. We herein describe a case of RC11 with clinical features of 11q-syndrome and endocrine abnormalities that have not yet been reported. A 20-year-old female patient had facial dysmorphism, short stature, psychomotor developmental delays, a ventricular septal defect, and thrombocytopenia. Karyotyping demonstrated RC11 (46,XX,r(11)(p15q25)). This patient presented with clinical features that may be related to Jacobsen syndrome, which is caused by partial deletion of the long arm of chromosome 11. Regarding endocrine abnormalities, our patient presented with precocious puberty followed by severe hirsutism, androgenic alopecia, clitoromegaly, and amenorrhea, which were associated with overweight, type 2 diabetes mellitus (T2DM), and hyperinsulinemia; therefore, this case meets the diagnostic criteria for polycystic ovary syndrome. Endocrine abnormalities are rare in patients with RC11, and the association of RC11 with precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM has not been reported previously. We speculate that gene(s) located on chromosome 11 might be involved in the pathogenesis of these conditions. Despite the rarity of RCs, studies to correlate the genes located on the chromosomes with the phenotypes observed could lead to major advances in the understanding and treatment of more prevalent diseases.

Learning points

  • We hypothesize that the endocrine features of precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM might be associated with 11q-syndrome.

  • A karyotype study should be performed in patients with short stature and facial dysmorphism.

  • Early diagnosis and adequate management of these endocrine abnormalities are essential to improve the quality of life of the patient and to prevent other chronic diseases, such as diabetes and its complications.

Open access

A Deeb, O Afandi, S Attia and A El Fatih

Summary

3-M syndrome is a rare autosomal recessive disorder caused by mutations in the CUL7, OBSL1 and CCDC8 genes. It is characterised by growth failure, dysmorphic features and skeletal abnormalities. Data in the literature show variable efficacy of GH in the treatment of short stature. We report four Emirati siblings with the condition. The index case is a 10-year-old boy with characteristic features, including prenatal and postnatal growth failure, a triangular face, a long philtrum, full lips and prominent heels. Genetic testing confirmed a novel mutation (p.val88Ala) in the CUL7 gene. The parents are healthy, first-degree cousins with nine children, of whom two died in the first year of life with respiratory failure. Both had low birth weight and growth retardation. The boy's older sibling reached an adult height of 117 cm (−6.71 SDS). She was never treated with GH. He was started on GH treatment at 7 years of age, when his height was 94 cm (−5.3 SDS). 3-M syndrome should be considered in children with short stature who have associated dysmorphism and skeletal abnormalities. The diagnosis is more likely to occur in families that have a history of consanguinity and more than one affected sibling. Death in early infancy due to respiratory failure is another clue to the diagnosis, which might have a variable phenotype within a family. Genetic testing is important for confirming the diagnosis and for genetic counselling. GH treatment might be beneficial in improving stature in affected children.

Learning points

  • 3-M syndrome should be considered in families that have more than one sibling with short stature, particularly if there is consanguinity.

  • Syndrome phenotype might be variable within a family with the same mutation.

  • Genetic analysis is helpful in confirming diagnosis in the presence of variable siblings' phenotype.

  • GH treatment might be useful in improving stature in 3-M syndrome.