Richard Stanhope

A frameshift mutation in MC4R associated with dominantly inherited human obesity

T he melanocortin-4 receptor (MC4R) is a G-protein coupled, seven-trans-membrane receptor which is highly expressed in the hypothalamus, a region of the brain intimately involved in appetite regulation 1. It is a high-affinity receptor for αMSH, a product of the pro-opiomelanocortin (POMC) gene, which inhibits feeding when administered to rodents 2. Hypothalamic POMC neurons are stimulated by leptin, an adipocyte-specific hormone which regulates appetite and energy expenditure, and constitute a link between leptin and the melanocortin system. Mc4r-deficient mice are hyper-phagic, severely obese, hyperinsulinaemic and show increased linear growth 3. Mice heterozygous for a null Mc4r allele exhibit weight gain intermediate to that seen in wild-type and homozygous mutant litter-mates. Additionally, ectopic expression in the brain of agouti 4 and agouti-related transcript 5 , natural antagonists of the MC4R ligand, αMSH, results in obesity in rodents. In humans, obesity syndromes associated with abnormalities in POMC (ref. 6) and prohormone processing defects involving POMC (ref. 7) have also been described. We have identified a cohort of severely obese children in whom no evidence for a recognized clinical syndrome or a structural hypothalamic cause for their obesity has been found. All are severely obese (mean body mass index (weight/height 2) is 34 kg/m 2) from an early age (<10 years). Sixty-three of these subjects were screened for mutations in MC4R by direct nucleotide sequencing. We identified one subject who was heterozygous for a 4-bp deletion at codon 211 (Fig. 1b). This results in a frameshift that introduces five aberrant amino acids culminating in a stop codon in the region encoding the fifth transmembrane domain, resulting in a truncated protein. As residues at the base of the fifth and sixth transmembrane domains are needed for G-protein binding and activation 8 , this mutation is likely to result in a non-functional receptor. No mutations were found in the 62 other subjects studied. The index patient II.1 (Fig. 1a) is four years old and is the only child from a non-consanguinous union. His weight is 32 kg (>99th centile), height 107 cm (91st cen-tile) and body mass index (BMI) is 28 kg/m 2 (>99th centile). His birthweight was 3.8 kg (50th centile), and progressive weight gain was noted from the age of four months (Fig. 2a). There is no clinical or biochemical evidence of adrenal or thyroid disease, the subject has a normal karyotype and intellectual development is normal. There is a history of hyperphagia …

The spectrum of Silver-Russell syndrome : a clinical and molecular genetic study and new diagnostic criteria

The Silver-Russell syndrome (SRS) is characterised by severe intrauterine growth retardation, with a preserved head circumference, leading to a lean body habitus and short stature. Facial dysmorphism and asymmetry are considered typical features of the syndrome, although the range of phenotypic variance is unknown. Fifty seven subjects varying in age from 0.84 to 35.01 years, in whom the diagnosis of SRS had been considered definite or likely, were re-evaluated in a combined clinical and molecular study by a single observer (SMP).  In 50 patients the clinical findings complied with a very broad definition of SRS. Notable additional findings included generalised camptodactyly seen in 11 (22%), many with distal arthrogryposis. Thirteen of the 25 males required genital surgery for conditions including hypospadias and inguinal hernia.  Fourteen (36.8%) subjects above school age have received a statement of special educational needs.  Molecular genetic analysis was performed in 42 subjects and has identified maternal uniparental disomy of chromosome 7 in four. The phenotype was generally milder with birth weights for one patient above and three below −2 SD from the mean. Two children had classical facial dysmorphic features, and two had a milder facial phenotype. Of relevance to the possible molecular mechanism underlying this condition, none of the four disomic patients had significant asymmetry.

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization*

OBJECTIVE The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmanns syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X‐linked‐KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X‐linked‐KS.

Phenotypic variability in 17β‐hydroxysteroid dehydrogenase‐3 deficiency and diagnostic pitfalls

Objective  17β‐hydroxysteroid dehydrogenase type 3 isoenzyme (17β‐HSD3) is required to produce testosterone for male sex differentiation. Mutations in the HSD17B3 gene cause 17βHSD3 deficiency and result in XY sex reversal of varying degree. We report the phenotypes of 14 subjects with 17βHSD3 deficiency in relation to sex of rearing, androgen production, and HSD17B3 mutations.

A new stress-related syndrome of growth failure and hyperphagia in children, associated with reversibility of growth-hormone insufficiency

BACKGROUND Growth failure without organic aetiology but associated with behavioural disturbance and psychosocial stress has been termed psychosocial short stature. This condition is not a valid diagnostic entity, but encompasses failure to thrive, stunting secondary to chronic malnutrition, and idiopathic hypopituitarism. Some children show spontaneous catch-up growth when removed from the source of stress, without further treatment, but until now precise definition of this subgroup for the purpose of clinical identification has not been possible. METHODS Hospital-referred children with growth failure unrelated to organic pathology, who came from stressful homes, were compared with children of short-normal stature identified from an epidemiological survey (n = 31). Growth-hormone dynamics were studied in the hospital group by a combination of diurnal profiles and provocation tests. The tests were repeated after a hospital stay of 3 weeks away from familial stress. Standard behavioural measures were obtained from home and school. FINDINGS In a distinctive subgroup (n = 29), growth-hormone insufficiency was associated with characteristic behavioural features, especially hyperphagia and polydipsia, and a normal body-mass index. When the children were removed from their stressful home circumstances, growth-hormone insufficiency spontaneously resolved only in formerly hyperphagic subjects. 74% of the non-hyperphagic cases (n = 23) were anorexic, with a low body-mass index and normal growth-hormone responses to provocation tests. INTERPRETATION We present explicit behavioural and developmental criteria by which the novel syndrome of hyperphagic short stature may be recognised clinically. Such children have a capacity for spontaneous recovery of growth-hormone production on removal from or reduction of stress. Discriminant and predictive validity of the core symptoms are demonstrated. Preliminary familial studies indicate a possible genetic predisposition.

Pituitary dysfunction, morbidity and mortality with congenital midline malformation of the cerebrum

Abstract The purpose of this study was to review systematically a series of patients with congenital midline brain defects and pituitary dysfunction in early childhood and to quantitate the degree of dysfunction and clinical outcome. This study was a retrospective analysis of case notes of patients with pituitary dysfunction associated with either a midline cerebral anomaly and/or optic nerve hypoplasia. Forty patients were studied: 2 with semilobar holoprosencephaly, 2 with lobar holoprosencephaly, 18 with septo-optic dysplasia with an intact septum pellucidum, 7 with septo-optic dysplasia with an absent septum pellucidum, 7 with agenesis of the corpus callosum and 4 patients with isolated pituitary hypoplasia. An early age of diagnosis, feeding difficulties, neurodevelopmental disability, visual impairment and seizures were common occurrences. Despite disordered neuro-anatomy, most seizure disorders were caused by hypoglycaemia or hypernatraemia. Hypotensive/hypoglycaemic crises accounted for two out of three deaths within the study population. Most of patients had multiple pituitary hormone deficiency with growth hormone and Adreo corticotrophic hormone deficiency occurring most commonly. Unequivocal isolated hypothalamic dysfunction was an uncommon finding. In congenital midline brain malformation there is a spectrum of disordered neuro-anatomy associated with variable pituitary dysfunction. Clinical manifestations such as convulsions and developmental delay may be due to disordered metabolism and/or neuro-anatomy. Conclusion Children with congenital midline brain defects frequently manifest convulsions, neurodevelopmental disability and poor growth due to disordered metabolism and/or neuro-anatomy. Treating clinicians must be aware of the complex, dynamic neurological and metabolic nature of these patients and their potential for early demise.

Reversibility of physiological growth hormone secretion in children with psychosocial dwarfism

OBJECTIVES Reversibility of GH insufficiency with a change of environment is characteristic of psychosocial dwarfism, and excludes an organic endocrinopathy. However, the change in GH pulsatility has not previously been described. We therefore wished to study spontaneous GH secretion before and after change to a more favourable environment in 11 children with psychosocial deprivation and short stature in order to evaluate if separation from the families can modify their patterns of GH secretion.

The Effects of Growth Hormone Therapy on Spontaneous Sexual Development

We have carried out a prospective randomised study in 52 (46 male, 6 female) children with isolated growth hormone (GH) deficiency treated with a GH regimen of 15 IU/m2/week administered as a daily subcutaneous injection. At the onset of the pubertal growth spurt, the patients were randomised to receive either an unaltered regimen (26 males, 1 female) or 30 IU/m2/week (20 males, 5 females). There was no change in the frequency of GH administration. The number of females in this study was too small to give a meaningful result. In contrast, the boys treated with either dose regimen showed no significant alteration in growth rate, but there was a faster than normal progression in pubertal maturation. It is concluded that the optimum final height of children with isolated GH deficiency may not be achieved in patients without the therapeutic manipulation of the onset and/or duration of puberty. 16 short normal children (9 males, 7 females) were treated with GH in a regimen of 25 IU/m2/week (range: 20-30) as a daily subcutaneous injection. The mean age for the onset of GH treatment was 11.5 and 11.0 years in the boys and girls, respectively. Our data suggest that both boys and girls had a more rapid rate of pubertal maturation than normal. It may be that in terms of final height prognosis, the events of puberty related to GH treatment counterbalance the improvement in growth prognosis during prepuberty.

Studies of gonadotrophin pulsatility and pelvic ultrasound examinations distinguish between isolated premature thelarche and central precocious puberty

We have studied the pulsatile secretion of gonadotrophins at night and made ovarian ultrasound examinations in three girls with central precocious puberty and three with isolated premature thelarche. The three girls with precocious puberty had well-defined pulsatile secretion of LH and FSH with LH predominating, as would be expected in normal puberty. Pulsatile secretion of gonadotrophins was also seen in girls with premature thelarche but the pattern was reversed. In girls with precocious puberty, large “multicystic” ovaries and large uteri were seen on ultrasound examination, whereas girls with isolated premature thelarche had small uteri and ovaries with less than four “cysts” up to 15 mm in diameter. These data provide the key to understanding the aetiology of isolated premature thelarche.

GH Treatment Induces Sustained Catch-Up Growth in Children with Intrauterine Growth Retardation: 7-Year Results

The anthropometric response to 7 years of GH treatment was assessed in 11 short children with Russell-Silver syndrome (RSS) and in 5 with non-dysmorphic intrauterine growth retardation (NRSS). GH treatment induced a significant increase (p < 0.0001) in the mean height standard deviation score (SDS) and at the 7-year follow-up a height appropriate for the natural history of final stature in NRSS/RSS was already attained. An appreciable growth rate was still present with final height being attained only in 2 girls. There was no significant change in height SDS for bone age. Multiple regression analysis showed only chronological age at the onset of GH treatment was a predictor of gain in height SDS during GH therapy. These findings suggest that early GH treatment improves long-term growth in children with NRSS/RSS. Moreover, final height attainment is required for a definitive assessment of the beneficial effect on adult stature. Bone age assessment is not a reliable parameter to predict final height outcome in these children.