Noha Musa

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Significance Congenital adrenal hyperplasia resulting from mutations in the CYP11B1 gene, which encodes a steroidogenic enzyme 11β-hydroxylase, is a rare inherited disorder associated with hyperandrogenemia, short stature, hypertension, and virilization of female newborns. We present a comprehensive clinical, genetic, and hormonal characterization for 68 of 108 patients with a genotype from an International Consortium on Rare Steroid Disorders. We also use computational modeling to define the effect of each of the missense mutations on the structure of 11β-hydroxylase, information that can be used to predict clinical severity prenatally in high-risk mothers. Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.

Assessment of health-related quality of life in Egyptian adolescents with type 1 diabetes: DEMPU survey

Abstract Background: Type 1 diabetes (T1D) is a serious chronic illness that imposes significant morbidity and mortality with a major impact on the quality of life (QoL) that became a core issue in diabetes care. Understanding the effect of diabetes on QoL is important for day-to-day clinical management and also for public health policy initiatives aiming at improving health outcomes for those with diabetes. The objective of the study was to assess the QoL in adolescents with T1D and assess the applicability of the use of the “Quality of Life for Youth” questionnaire at the Diabetes, Endocrine and Metabolism Pediatric Unit (DEMPU) clinic. Methods: One hundred and fifty adolescents (82 males and 68 females) (10–18 years), with T1D of at least 1 years’ duration, completed the questionnaire that evaluated symptoms related to diabetes, treatment, activities, parent issues, worries about diabetes and health perception. Higher scores indicated a more negative impact of diabetes and poorer QoL. Results: Males showed a significantly better mean QoL score than females (p=0.004). Different age groups showed different QoL scores (p=0.047). Urban adolescents had a better QoL than rural counterparts (p=0.02). Adolescents with poor QoL had generally lower educational level (p=0.02). Better metabolic control was associated with a better QoL (p=0.01). However, duration of diabetes and body mass index (BMI) had no statistically significant effect on QoL. Conclusions: QoL had a variable significant association with certain socio-demographic and clinical characteristics of diabetics (sex, residence, educational level as well as metabolic control).

Vitamin D status in Egyptian children with type 1 diabetes and the role of vitamin D replacement in glycemic control.

Abstract Background: The association of low serum 25 hydroxy cholecalciferol (25OHD) levels with high glucose level and diminished insulin sensitivity suggests that vitamin D (VD) may modulate insulin metabolism. The aim of the study was to screen for vitamin D deficiency (VDD) in pediatric patients with type 1 diabetes (T1D) and study the effect of VD supplementation on their glycemic control and insulin requirements. Methods: A prospective cohort study including 50 patients with T1D. VD level was assessed initially and after 3 months of VD supplementation (in those with VDD). HbA1c and insulin requirements were studied at 0, 3 and 6 months of supplementation. Results: Fifty patients with T1D were included with mean diabetes duration of 4.11±2.34 years. VD level ranged from 0.2 to 33 ng/mL. VD status correlated significantly with daily insulin dose (p=0.030, r=0.306) and HbA1c (p<0.001, r=0.243). Thirty-five patients (70%) had VDD and were allocated for VD supplementation for 3 months. The mean HbA1c improved significantly after supplementation (p=0.003), followed by a significant deterioration at 6 months with no change in their insulin requirements at 3 or 6 months. Conclusions: VD was highly prevalent in Egyptian T1D patients. VD supplementation improved glycemic control at 3 months after therapy with no reduction in insulin requirements.

Timing and Outcome Concerns regarding Feminizing Genitoplasty from the Perspective of Egyptian Families of Girls with Virilized External Genitalia.

Background: Congenital adrenal hyperplasia in females leads to virilization of external genitalia and persistent urogenital sinus. There are controversies regarding the timing and outcomes of surgery. Deferring surgeries beyond childhood is difficult to implement in conservative societies, and may result in stigmatization and distress to individuals with disorders of sexual differentiation and their families. Methods: Thirty girls with virilization due to congenital adrenal hyperplasia were admitted for single-stage feminizing genitoplasty, between 2011 and 2014. We prospectively studied the concerns and input of the families represented by the mothers. After comprehensive counselling, the mothers completed a questionnaire to clarify their priorities and concerns related to surgery. Results: Surgeries were performed at a mean age of 22 months. Most cases ranged between Praders degrees III and IV. Egyptian families believe that early surgical reconstruction is in the best interest of their girls. They are marginally more concerned about functional outcomes and future child bearing than external appearance and cosmetic outcomes. Conclusions: Social difficulties noticeably add challenges to the management plan within conservative societies. Early genital reconstructive surgery, when reasonably indicated, needs to remain a viable option. Comprehensive psychosocial support within a multidisciplinary approach is needed to defer feminizing genitoplasty in selected cases to adolescence.

A study of familial Mediterranean Fever (MEFV) gene mutations in Egyptian children with type 1 diabetes mellitus.

BACKGROUND/AIMS An association of type 1 DM and familial Mediterranean fever (FMF) has been newly reported in the medical literature. The aim of the present work was to investigate frequency of MEFV gene mutations in Egyptian children with type 1 diabetes mellitus. METHODS Forty five children with type 1 DM were screened for Mediterranean Fever (MEFV) gene mutation. Forty one healthy control subjects were included. Identification of FMF gene mutation was done based on polymerase chain reaction (PCR) and reverse hybridization. The assay covers 12 mutations in the FMF gene: E148Q - P369S - F479L - M680I (G/C) - M680I (G/A) - I692del - M694V - M694I - K695R-V726A - A744S and R761H. RESULTS Among the screened diabetics, the overall frequency of MEFV gene mutations was 42.2% and among the control group it was 34.1% with no significant difference. Fourteen out of 45 diabetic children (31.1%) were heterozygous (E148Q in 7 children, A744S in 3 children, V726A in 2 children, M680I (G/C) in 1 child and P369S in1 child), while 5 children (11.1%) were compound heterozygous (M694V/M694I in 2 children, E148Q/K695R mutations in 1 child, E148Q/M694I in 1 child and E148Q/V726A in 1 child). The control group showed heterozygous mutation in 34.1% of cases (E148Q mutation in 14.6%, V726A in 12.2%, M680I (G/C) in 4.9% and M694V in 2.4%). CONCLUSION No significant difference in mutation frequency between diabetic and non-diabetic children. We have high carrier rate of MEFV gene mutations among Egyptian population probably due to high consanguinity.

CYP21A2 genetic profile in 14 Egyptian children with suspected congenital adrenal hyperplasia: a diagnostic challenge

CYP21A2 genotyping remains an important element in the diagnosis and management of congenital adrenal hyperplasia, and establishing accurate genotype–phenotype correlations has facillitated adequate genetic counseling and prenatal management for at‐risk families. Despite extensive efforts to establish a clear genotype–phenotype correlation, some discordance remains. Establishing a diagnosis of congenital adrenal hyperplasia on the basis of biochemical and clinical data is occasionally challenging, and the identification of CYP21A2 mutations may help confirm the diagnosis. We review the diagnostic challenges despite an extensive genetic evaluation for 14 patients with a suspected clinical and biochemical diagnosis of congenital adrenal hyperplasia. Other diagnostic entities should be considered in the absence of convincing genetic data.