Assunta Albanese

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.

Suppression of menstruation in adolescents with severe learning disabilities

As girls with severe cognitive developmental delay progress into puberty and become young women with learning disabilities, concerns about menstruation are common amongst carers and health care professionals are often consulted for advice. Very little, however, has been published on this area to guide the practitioner and studies are almost exclusively confined to the gynaecological literature. We aim to give an account of the various therapeutic options available and current practice within the paediatric endocrinology unit at our institution.

Organ-specific management and supportive care in chronic graft-versus-host disease

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ‐specific complications of chronic graft‐versus‐host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse.

Effect of Long-Term Growth Hormone Treatment on Final Height of Children with Russell-Silver Syndrome

Background: The aim of this study was to determine the beneficial effects of long-term growth hormone (GH) treatment on final height (FH) in 26 children with Russell-Silver syndrome (RSS). Methods: Twenty-six patients (16 males) were diagnosed with RSS at a median age of 2.9 years according to clinical criteria. All patients were prepubertal at the commencement of treatment. They received treatment with biosynthetic human GH for 9.8 years (median) and all attained FH. Results: The median height at the commencement of treatment was –2.7 SDS and increased to –1.3 SDS (p = 0.001). However, FH did not reach target height (–0.90 SDS, p = 0.003). Predictors of FH outcome were: the height at the start of treatment (r2 = 0.419, p < 0.001) (inversely related) and the height gain at onset of puberty (r2 = 0.257, p < 0.001) (positively related). The overall prediction model accounted for 67.6% of height gain. Sitting height improved gradually during GH treatment (–3.3 to –1.0 SDS, p = 0.012), as did weight (–3.3 to –1.3 SDS, p < 0.001) and BMI (–1.5 to –0.2 SDS, p < 0.001). Conclusions: A significant improvement of growth in RSS children has been shown after 10 years of GH treatment with a FH of –1.3 SDS. The shorter the patient at the start of treatment is, the greater the increment in FH. A significant response is also shown at the onset of puberty. GH treatment may also have a beneficial effect on the spinal length of RSS children.

Primary hypothyroidism in a child mimicking a pituitary macroadenoma

We report the case of an 11-year-old girl with primary autoimmune hypothyroidism causing secondary pituitary enlargement. She presented with headaches and a pituitary mass on MRI thought to be due to a pituitary macroadenoma. Resolution of the pituitary mass and symptoms occurred with thyroxine therapy. It is mandatory to rule out primary hypothyroidism as a cause of pituitary enlargement before surgery is considered.

The Use of a Computerized Method of Bone Age Assessment in Clinical Practice

We assessed the reliability and repeatability of a new computerized bone age system, both versions 3.4 and 3.5 (licensed by Discerning System Inc. and Ares Service SA, Serono), able to automatically assess bone age on a left hand and wrist radiograph. This computer system is based upon Tanner and Whitehouses method (TW2), but there are important differences. Our sample included an initial group of 40 patients who had growth delay/constitutional delay of growth and puberty (n = 10), growth hormone insufficiency/deficiency (n = 15), low birth weight/Silver-Russell syndrome (n = 9), precocious puberty (n = 6), as well as 20 patients with various skeletal dysplasias (multiple epiphyseal dysplasia n = 7, pseudoachondroplasia n = 7, acrodysostosis n = 5, achondroplasia n = 1), 7 girls with Turner syndrome, and 10 boys with nephrotic syndrome on chronic corticosteroid treatment. Multiple anthropometric readings of the same radiographs demonstrated excellent repeatability of the assessment. In addition, the number of times that a manual insertion of a grade was required was similar in four different assessments. The computerized method did not entirely avoid errors in interpretation as the position of the x-ray on the screen was critical. There was a high manual insertion rate in radiographs of children with skeletal dysplasia. However, the computer assessment system, version 3.5, performed adequately for radiographs of children with normal bone morphology and Turner syndrome and had the advantage of a continuous scale of assessment.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

Management of Electrolyte and Fluid Disorders after Brain Surgery for Pituitary/Suprasellar Tumours

Disturbances in salt and water balances are relatively common in children after brain surgeries for suprasellar and pituitary tumours, presenting diagnostic and therapeutic challenges. Although hypernatraemia associated with central diabetes insipidus is commonly encountered, it is hyponatraemia (HN) that poses more of a diagnostic dilemma. The main differential diagnoses causing HN are the syndrome of inappropriate antidiuretic hormone secretion, marked by inappropriate retention of water, and cerebral salt wasting, characterized by polyuria and natriuresis. Diagnosis and management can be even more difficult when these conditions precede or coexist with each other. These diagnostic and therapeutic dilemmas are discussed in detail in this review.

Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction.

IMPORTANCE A multiorgan syndromic disorder characterized by sideroblastic anemia, immunodeficiency, periodic fever, and developmental delay with an uncharacterized retinal dystrophy is caused by TRNT1. This report of a family with a homozygous mutation in TRNT1 expands the ocular phenotype to include cataract and inner retinal dysfunction and details a mild systemic phenotype. OBSERVATIONS A consanguineous family with 3 affected children was investigated. Key clinical features comprised hypogammaglobulinemia, short stature with microcephaly, cataract, and inner retinal dysfunction without sideroblastic anemia or developmental delay. Two siblings had poor balance and 1 sibling had sensorineural hearing loss. The oldest sibling had primary ovarian failure diagnosed at age 14.5 years. Exome sequencing identified a homozygous missense variant in TRNT1, c.295C>T (p.Arg99Trp) in all 3 patients. The sibling with hearing loss also harbored a homozygous mutation in GJB2, c.71G>A (p.Trp24*), which is an established cause of sensorineural hearing loss. CONCLUSIONS AND RELEVANCE This family expands the ocular and systemic phenotypes associated with mutations in TRNT1, demonstrating phenotypic variability and highlighting the need for ophthalmic review of these patients.

Reversible Growth Hormone Excess in Two Girls with Neurofibromatosis Type 1 and Optic Pathway Glioma

Background: A total of 12 children with neurofibromatosis type 1 (NF-1) with optic pathway glioma (OPG) and growth hormone (GH) excess are reported to date, but no data exist on the long-term outcome. We describe 2 girls with NF-1 with OPG and GH excess treated with somatostatin analogue (SSa) who maintained a normal GH axis after stopping SSa therapy. Methods: The diagnosis of GH excess was established from auxological data, persistently high levels of insulin-like growth factor 1 (IGF-1) and a lack of GH suppression during an oral glucose tolerance test. Results: Both patients were started on SSa treatment. During treatment, growth deceleration and normal IGF-1 levels were documented. The first case stopped treatment following the development of SSa side effects. The second case interrupted SSa when, closed to her final height, a normal IGF-1 level was documented. While off treatment, both cases maintained normal IGF-1 levels and appropriate growth velocity for their age and development, with normal GH secretion on biochemical testing. Both cases received treatment for central precocious puberty. Conclusion: GH excess in NF-1 children with OPG can be reversed and only short-term SSa therapy may be required. The aetiology remains undetermined, but the course suggests a hypothalamic dysfunction.