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We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.

BackgroundA newborn with ambiguous genitalia needs prompt evaluation to detect life-threatening conditions (e.g., salt-losing crisis in congenital adrenal hyperplasia [CAH]) and gender assignment. Sex assignment in these children continues to be a challenging diagnostic and therapeutic problem. We studied the causes and characteristics of ambiguous genitalia in children who were referred to a cytogenetic laboratory.Patients and MethodsWe retrospectively reviewed a total of 120 medical records of patients with a primary indication of ambiguous genitalia that were referred to the cytogenetic lab for karyotyping during the period of 1989 to 1999. Diagnosis was based on a clinical impression from the primary physician, who was primarily a staff pediatrician, endocrinologist and/or pediatric urologist.ResultsCAH was the underlying cause of ambiguous genitalia in 41 of 63 patients with ambiguity due to endocrine causes; 39 of these patients showed a 46,XX karyotype and 2 cases were 46,XY (both the 46,XY patients had 3 β-hydroxylase deficiency). In 57 patients, ambiguous genitalia were due to congenital developmental defects. The most common endocrine case of ambiguous genitalia was 21-OH deficiency. Seven patients were classified as idiopathic with six showing the 46,XY and one the 46,XX karyotype. Gender was reassigned at birth or at diagnosis in 15 patients.ConclusionThe etiology of ambiguous genitalia is variable. The physician managing these families could minimize the trauma of having a child with unidentified sex by providing appropriate genetic counseling so that the parents can make an early decision. Prenatal DNA testing in at-risk families should be considered and appropriate therapy offered to minimize or prevent genital ambiguity.

BACKGROUND: Screening for congenital hypothyroidism (CH) using cord blood or heel-stick samples is considered essential for the prevention of long-term complications CH, which include intellectual disability and slow growth.OBJECTIVE: Compare the sensitivity and specificity of cord blood and heel-stick samples for determining thyroid-stimulating hormone (TSH) levels for the detection of CH.DESIGN: Comparative diagnostic accuracy.SETTINGS: Tertiary care center in Riyadh.PATIENTS AND METHODS: The study included all infants who were delivered during the period from May 2011 to May 2013. As part of routine newborn screening, both cord blood and heel-stick samples were collected from each newborn for CH screening by measuring TSH levels. A cord TSH level was considered positive if the concentration of TSH was more than 60 mIU/L and negative if less than 30 mIU/L. Any cord TSH level between 30-60 mIU/L was considered borderline, and free T4 was measured from the same cord sample. The result was considered positive if the free T4 level was below 9 pmol/L. Heel-stick TSH levels more than 20 µU/L were considered positive. All newborns with positive results were recalled and a peripheral venous sample was taken for TSH and free T4 for confirmation.MAIN OUTCOME MEASURES: Sensitivity and specificity, positive and negative predictive values and recall rates.SAMPLE SIZE: 17 729 screened babies.RESULTS: Of 17 729 neonates screened, 7 were diagnosed as having primary CH. All confirmed cases were detected by both cord and heel-stick TSH levels: 88 cord results were positive (sensitivity 100%, specificity 99.6%, with a recall rate of 0.04%) and 305 heel-stick results were positive (sensitivity 100%, specificity 98.3%, with a recall rate of 1.68%).CONCLUSION: Both cord and heel-stick TSH testing detected all cases of CH. Cord testing was superior to heel-stick testing as the recall rate was lower. We think cord TSH testing is preferable when heel-stick is difficult or early discharge is the practice.LIMITATIONS: Retrospective; the timing of newborn screening for TSH sampling was premature.CONFLICT OF INTEREST: None.

The objective of this study is to investigate the effects of IDDM on the function of the auditory pathway from the cochlea to the auditory cortex in child patients. Totally, 140 ears of 70 children with IDDM and 60 ears of 30 age and gender-matched healthy controls were included in the study. The ages of patients and controls ranged from 4 to 14 years. Audiological assessment including pure-tone audiometry, otoacoustic emission testing (OAE) and auditory brainstem response testing (ABR) has been performed to all participants. There was no significant difference between the patients and controls regarding pure-tone thresholds on audiometry (p > 0.05). The latencies of waves I, III and V on ABR were not significantly different between the patients and controls (p > 0.05). The amplitudes on DPOAE testing obtained from both groups were not significantly different at the frequencies of 2,000 and 4,000 Hz (p > 0.05). However, the DPOAE amplitudes of the patients at 1,000 Hz were significantly lower than those of controls at the same frequency (p = 0.03). There was no difference between the patients who had chronic disease (>5 years) and healthy controls regarding pure-tone audiometry, ABR and DPOAE testing results (p > 0.05). In the light of the findings obtained with pure-tone audiometry, and OAE and ABR testing, it seems that auditory system is spared in children with IDDM at clinical level. Diabetes control and chronicity of the disease do not impact on the auditory system except for a subclinical involvement in the apical portion of the cochlea.

A 6-year-old girl had a group A beta-haemolytic streptococcal (GABS) throat infection and Henoch-Schonlein purpura (HSP). The clinical course was complicated by nephrotic syndrome due to crescentic glomerulonephritis, transient neurological symptoms due to focal ischaemia of the brain, and congestive cardiac failure due to myocarditis. The clinical presentation highlights the diversity of systemic involvement in HSP, the transient nature of apparently serious central nervous system involvement, and a possible role of GABS in its aetiology.

We conclude that sirolimus is less effective in the treatment of diffuse CHI in patients with severe mutations in the homozygous state compared with those with the mutations in the heterozygous.

Puberty is the gradual transition period between childhood and adulthood. Many factors may contribute to the onset of puberty. The objective of the study was to determine the age of onset of secondary pubertal characteristics among Saudi Arabian girls. A cross-sectional study was conducted using a cluster sample design. Seven hundred and twenty-five schoolgirls between the ages of 6 and 16 years from diverse socioeconomic levels were included. During physical examinations, the height and weight of the girls were recorded, and the stages of breast and pubic hair development were determined according to Tanner stages; axillary hair development was determined according to modified stages. The median age at Tanner stage 2 for breast and pubic hair development was 10 years. The median age at stage 2 in modified scales for axillary hair development was 12 years. In conclusion, the median age of the onset of breast development at Tanner stage 2 for Saudi girls in Riyadh is lower than what has been reported in some countries in Europe, South Africa, Turkey and India but similar to girls in Hong Kong, China and white girls in the USA, which may support secular trends of an earlier onset of puberty.