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Open access

Jasmeet Kaur, Alan M Rice, Elizabeth O’Connor, Anil Piya, Bradley Buckler and Himangshu S Bose

Congenital adrenal hyperplasia (CAH) is caused by mutations in cytochrome P450 side chain cleavage enzyme (CYP11A1 and old name, SCC). Errors in cholesterol side chain cleavage by the mitochondrial resident CYP11A1 results in an inadequate amount of pregnenolone production. This study was performed to evaluate the cause of salt-losing crisis and possible adrenal failure in a pediatric patient whose mother had a history of two previous stillbirths and loss of another baby within a week of birth. CAH can appear in any population in any region of the world. The study was conducted at Memorial University Medical Center and Mercer University School of Medicine. The patient was admitted to Pediatric Endocrinology Clinic due to salt-losing crisis and possible adrenal failure. The patient had CAH, an autosomal recessive disease, due to a novel mutation in exon 5 of the CYP11A1 gene, which generated a truncated protein of 286 amino acids compared with wild-type protein that has 521 amino acids (W286X). Although unrelated, both parents are carriers. Mitochondrial protein import analysis of the mutant CYP11A1 in steroidogenic MA-10 cells showed that the protein is imported in a similar fashion as observed for the wild-type protein and was cleaved to a shorter fragment. However, mutant’s activity was 10% of that obtained for the wild-type protein in non-steroidogenic COS-1 cells. In a patient of Mexican descent, a homozygous CYP11A1 mutation caused CAH, suggesting that this disease is not geographically restricted even in a homogeneous population.

Learning points:

  • Novel mutation in CYP11A1 causes CAH;
  • This is a pure population from Central Mexico;
  • Novel mutation created early truncated protein.

Open access

Asma Deeb, Hana Al Suwaidi, Salima Attia and Ahlam Al Ameri

Summary

Combined17α-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia and hypogonadism. Hypertension and hypokalemia are essential presenting features. We report an Arab family with four affected XX siblings. The eldest presented with abdominal pain and was diagnosed with a retroperitoneal malignant mixed germ cell tumour. She was hypertensive and hypogonadal. One sibling presented with headache due to hypertension while the other two siblings were diagnosed with hypertension on a routine school check. A homozygous R96Q missense mutation in P450c17 was detected in the index case who had primary amenorrhea and lack of secondary sexual characters at 17 years. The middle two siblings were identical twins and had no secondary sexual characters at the age of 14. All siblings had hypokalemia, very low level of adrenal androgens, high ACTH and high levels of aldosterone substrates. Treatment was commenced with steroid replacement and puberty induction with estradiol. The index case had surgical tumor resection and chemotherapy. All siblings required antihypertensive treatment and the oldest remained on two antihypertensive medications 12 years after diagnosis. Her breast development remained poor despite adequate hormonal replacement. Combined 17α-hydroxylase/17,20-lyase deficiency is a rare condition but might be underdiagnosed. It should be considered in young patients presenting with hypertension, particularly if there is a family history of consanguinity and with more than one affected sibling. Antihypertensive medication might continue to be required despite adequate steroid replacement. Breast development may remain poor in mutations causing complete form of the disease.

Learning points

  • Endocrine hypertension due to rarer forms of CAH should be considered in children and adolescents, particularly if more than one sibling is affected and in the presence of consanguinity.
  • 17α-hydroxylase/17,20-lyase deficiency is a rare form of CAH but might be underdiagnosed.
  • Blood pressure measurement should be carried out in all females presenting with hypogonadism.
  • Anti-hypertensive medications might be required despite adequate steroid replacement.
  • Initial presenting features might vary within affected members of the same family.
  • Adverse breast development might be seen in the complete enzyme deficiency forms of the disease.

Open access

Chrisanthi Marakaki, Anna Papadopoulou, Olga Karapanou, Dimitrios T Papadimitriou, Kleanthis Kleanthous and Anastasios Papadimitriou

Summary

11β-hydroxylase deficiency (11β-OHD), an autosomal recessive inherited disorder, accounts for 5–8% of congenital adrenal hyperplasia. In Greece, no cases of 11β-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11-deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11β-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens.

Learning points

  • 11β-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5–8% of cases with an incidence of 1:100 000–1:200 000 live births in non-consanguineous populations.
  • Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reported
  • Regarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls.
  • Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients.
  • Diagnosis lies upon elevated 11-deoxycortisol and DOC plus upstream precursors, such as 17α-hydroxyprogesterone and Δ4-androstenedione.
  • The established treatment of steroid 11β-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms.