Objective P450 side‐chain cleavage deficiency (SCCD) patients present with primary adrenal insufficiency (PAI) with or without undervirilized external genitalia. The distinction between classic and nonclassic steroidogenic acute regulatory protein deficiency has been described, whereas in SCCD is unclear. The data on gonadal function and its correlation with SCCD genotype has not been studied. We describe our experience and perform a systematic review of genetically proven SCCD patients to determine the distinct phenotypic and genotypic characteristics of 46,XY SCCD patients with typical male external genitalia (SCCD‐TMG) and atypical (SCCD‐AG) external genitalia. Design, Patients and Measurements Retrospective review of three genetically proven SCCD patients from our centre and per‐patient data analysis from a systematic review of 52 probands was performed. SCCD‐TMG (n = 19) was defined as external genitalia of Sinnecker score 1 with 46,XY karyotype; the rest (Sinnecker 2–5) were classified as SCCD‐AG (n = 15). Results We report two new Indian cases of SCCD with three novel likely pathogenic variants and pubertal follow‐up of a previously reported patient. In systematic review, age at diagnosis of PAI and elevated renin were not different between 46,XY SCCD‐TMG (n = 19) and SCCD‐AG (n = 15), whereas spontaneous puberty (9/9 vs. 0/3, p = .0045), normal prepubertal (5/5 vs. 6/6, p = .002), pubertal gonadotropins (2/9 vs. 0/3, p = 1) and normal pubertal testosterone (9/11 vs. 0/3, p = .027) were more common in SCCD‐TMG. Testicular adrenal rest tumours were exclusive to SCCD‐TMG (n = 4). SCCD‐TMG was associated with four particular genotypes [monoallelic p.Glu314Lys with another deleterious variant on the second allele (p.Glu314Lys/X‐CHS: X‐compound heterozygous state), biallelic p.Arg451Trp, p.Phe215Ser/p.Arg232Ter and monoallelic p.Val79Ile]. 46,XX SCCD patients with p.Glu314Lys/X‐CHS also had normal gonadotropins with spontaneous puberty. Conclusion SCCD‐TMG is associated with four specific genotypes and distinct gonadal characteristics from SCCD‐AG with overlapping features of PAI.
Background: side-chain cleavage deficiency (SCCD) patients present with primary adrenal insufficiency (PAI) with or without under virilized external genitalia. Distinction between classic and nonclassicalsteroidogenic acute regulatory protein (StAR) deficiency has been described, whereas in SCCD is unclear. The data on gonadal function and its correlation with SCCD genotype has not been studied. Objectives: We describe our experience and perform a systematic review of genetically-proven SCCD patients to determine the distinct phenotypic and genotypic characteristics of 46XY SCCD patients with typical male external genitalia (SCCD-TMG) and atypical (SCCD-AG) external genitalia. Methods: Retrospective review of three genetically proven SCCD patients from our center and per-patient data analysis from a systematic review of 52 probands was performed. SCCD-TMG (n = 19) was defined as external genitalia of Sinnecker score 1 with 46XY karyotype; the rest (Sinnecker 2-5) were classified as SCCD-AG (n = 15). Results: We report two new Indian cases of SCCD with three novel likely-pathogenic variants and pubertal follow-up of a previously reported patient. In systematic review, age at diagnosis of primary adrenal insufficiency (PAI), and elevated renin were not different between 46XY SCCD-TMG (n = 19) and SCCD-AG (n = 15) whereas spontaneous puberty (9/9 vs 0/3, p = 0.0045), normal prepubertal (5/5 vs 6/6, p = 0.002), pubertal gonadotropins (2/9 vs 0/3, p = 1), and normal pubertal testosterone (9/11 vs 0/3, p = 0.027) were more common in SCCD-TMG. Testicular adrenal rest tumors were exclusive to SCCD-TMG (n = 4). SCCD-TMG was associated with four particular genotypes[monoallelic p.Glu314Lys with another deleterious variant on the second allele (p.Glu314Lys/X-CHS: X-compound heterozygous state), biallelic p.Arg451Trp, p.Phe215Ser/p.Arg232Ter, and monoallelic p.Val79Ile]. 46XX SCCD patients with p.Glu314Lys/X-CHS also had normal gonadotropins with spontaneous puberty. Conclusion: SCCD-TMG is associated with four specific genotypes and distinct gonadal characteristics from SCCD-AG with overlapping features of PAI.
Background: Gonadotropin-dependent precocious puberty (GDPP) is the most common cause of precocious puberty. Data on GDPP from Indian subcontinent is scarce. Objectives: We aim to describe single centre experience of patients with GDPP. Methods: The clinical, biochemical features and therapeutic outcomes of patients presenting with diagnosis of GDPP from Jan 2000 to July 2021 were analyzed. Results: 78 patients (girls, n = 61, 78.2%) with GDPP were included. The median age of pubertal onset (29 vs. 75 months) and age at presentation (58 vs. 82 months) was earlier in boys than in girls. The commonest presenting symptom was genitalia growth (76.47%) in boys and breast development (75.4%) in females, followed by height spurt (boys: 17.6%, girls: 11.4%), pubic hair development (boys: 5.8%, girls: 6.5%) and vaginal bleeding (6.5%). The height at presentation and target height SDS were 1.02 and -0.77 in males and 0.75 and -0.82 in females, respectively. In boys, median (range) basal serum FSH, LH and testosterone were 2.48 mIU/ml (0.42-5.7), 2.6 mIU/ml (0.52-10.01), and 3.75 ng/ml (0.1-8.27) respectively. In girls, the median (range) basal serum FSH and LH were 5.24 mIU/ml (1.03-19.8) and 2.2 mIU/ml (0.05-15.8); basal serum LH being <0.3 mIU/ml was seen in 11 females. The median post gonadotropin stimulated peak serum LH in the latter 11 females (age range: 82-99 months) was 9.37 mIU/ml (range: 5.42-19 mIU/ml). At 60 minutes, all except one patient reached a stimulated serum LH value of ³ 5 mIU/ml. The median (range) difference in bone age and chronological age was 33 months (-2.0 to 98) and 2.5 months (4.0 to 76) in boys and girls, respectively. Ultrasonogram pelvis was available for 38 females. Uterine length ³ 3.2 cm was found in 84.2% of patients. In boys, precocity-related MRI brain abnormality was seen in 80% whereas it was found in 23.6% of girls. Fifty-five patients were treated with injection leuprolide acetate depot [monthly 3.75 mg per (n = 2) or 7.5 mg (n = 1), three monthly 11.25 mg (n = 27) or 22.5 mg (n = 25)] whereas five patients were treated with triptorelin. Only one girl had an allergic reaction to leuprolide and was switched to triptorelin. In males, final height SDS was 0.16 (n = 2); in females, final height SDS was -0.25 (n = 20). MPH SDS in treated patients were -0.38 and -0.86 in boys and girls, respectively. Conclusion: GDPP was more common in girls. Post gonadotropin stimulated peak serum LH ³5 mIU/ml at60 min aids in diagnosis in those with LH £0.3 mIU/ml. GnRH therapy helps in reducing height loss.
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