Diencephalic syndrome in childhood, a challenging cause of failure to thrive: miniseries and literature review

A 26-month-old boy was referred to the Gastroenterology and Nutrition Unit of Meyer Children’s Hospital for persistent failure to gain weight despite adequate caloric intake. He was fine until 18-month-old when he started to wake up scared during the night, walking around the house, and going back to sleep after few hours; subsequently, a deceleration of weight growth, despite an adequate caloric intake, was noticed, in absence of gastrointestinal or other symptoms. Baseline investigations towards malabsorption, including total protein, albumin and vitamins dosages, as well as celiac disease (CD) screening and fecal exams, were negative. Six months later, due to further decrease in weight growth, he was referred to a pediatric endocrinologist: hormonal evaluations including thyroid hormones and abdominal ultrasound were unremarkable. When admitted to our hospital no cardiac, thoracic and abdominal abnormalities were found, as well as the neurological exam and development resulted normal, except for an irritable behavior. In the last month, the child had started to walk around both at home and at the kindergarten also during the day, and he had presented motion sickness during journeys by car. The growth curve showed weight loss (from 25^th to < 3^rd percentile) started at18 months. His daily dietary intake, assessed through e 3-day-diary administered by our dietitian to the parents, was normal for age. Stool sample tests excluded bacterial, mycotic and parasitic infections; fecal calprotectin and routine blood tests together with nutritional values were normal. In the suspicion of endocranial tumor; abrain MRI was performed; a large supra-sellar lesion (diameters 44 × 40x38 mm) in hypothalamic-pituitary and chiasmatic region, was found, with enhancement after contrast infusion, compressing the cerebral peduncles, Willis’s polygon, chiasmatic optic tracts and third ventricle, with consequential hydrocephalus and lateral ventricles’ dilation. These results led to the final diagnosis of DS, seven months after FTT has begun. Ventriculo-peritoneal derivation (VPD) and mass biopsies were performed. After histological diagnosis of low-grade astrocytoma, the chemotherapy with carboplatin and etoposide was started, with initial weight gain. There was no indication of surgical treatment. The child did not receive either enteral or parenteral nutrition because he well-nourished himself, autonomously; our dietitian enriched his diet with hypercaloric supplements and checked his daily intake. During 6-months follow-up, MRI showed unvaried mass dimensions and impregnation. No endocrinological changes were detected during the follow-up and the child gained weight (25^th centile).

A 14-month-old girl was admitted to our hospital for poor weight gain, with normal caloric intake. She was exclusively breast-fed until 6 months, when weaning was started including gluten from the 7^th month; no allergies were documented. From the age of 8-month, a slight decrease in growth velocity was highlighted during a scheduled pediatric visit; no symptoms were noticed, except for occasional diarrhea; at evaluation, she presented with good appetite; no episode of vomiting, fever, sweating, or irritability occurred. A first attempt with cow’s milk-free diet resulted unsuccessful. Growth chart evidenced progressive weight loss, falling from 50 to 10^th percentile. Baseline investigations, including complete blood count (CBC), hepatic and renal function test, thyroid hormones, electrolytes, total protein and urine analysis were normal. CD screening and stool cultures were negative. At the age of 14 months, due to worsening in FTT, she was hospitalized. On admission, poor general conditions with severe weight loss (< 3^rd percentile), length 72 cm (5^th percentile) and normal head circumference (75^th percentile) were recorded. Pallor and lack of subcutaneous fat were evident. The child was otherwise well, alert, friendly and cooperating, and was achieving appropriate milestone. No abnormalities in neurologic, cardiac, thoracic, lymph nodes and abdominal examination were recorded. Laboratory work-up confirmed normal baseline investigations, excluding infections and intestinal malabsorption. The 3-days-food diary revealed an adequate caloric intake. Stool culture was negative for bacterial, mycotic, and parasitic infections. Peripheral blood smear evidenced normal count blood cell without acanthocytes. Sweat test and autoimmunity markers were negative. Chest X-ray, cardiac evaluation and abdomen echography were normal; hand X-ray confirmed appropriate skeletal age. Ocular examination described pigmented perineural ring without signs of papillary edema or vascular anomalies. During hospitalization, the child did not manifest any eating disorders and stools were normal. No episode of fever, vomiting, excessive sweating, bleeding disorders or neurologic signs appeared. Persisting weight loss along to normal investigations, brain MRI was performed to rule out the possibility of neoplasia, in the hypothesis of DS: a large, enhancing supra-sellar mass (diameters 40 × 36x31 mm) involving hypothalamic-pituitary region, extended to third ventricle with secondary lateral ventricle dilation was found. All these data suggest the final diagnosis of DS. After histologic diagnosis of low-grade astrocytoma, chemotherapy was started. Surgical resection (debulking) and radio therapy (RT) an were also performed. Her weight growth velocity slowly improved, reaching the 10^th percentile in 10 months (from < 3^rd percentile). Unfortunately, the child died 12 months after diagnosis, due to multiorgan failure and electrolyte imbalance (severe acute hypernatremia) resulting from progressive hypothalamic damage.

A 16-month-old male was hospitalized for severe FTT. He was a full-term new-born from a twin pregnancy complicated by gestational diabetes and systemic hypertension, without signs of intrauterine growth delay. For his first 6 months, he received an adequate caloric intake based on breastfeeding added with formula milk. At the weaning, a transient difficulty in swallowing solid foods was described, quickly normalized with achievement of a various diet. He regularly grew up (weight at 97^th percentile) until 8 months; since then, he presented a deceleration in weight gain, falling to 25^th percentile, despite a normal height growth, over 8-month-period. The child presented regular diuresis and normal stools; neurodevelopment milestones were properly attained. Blood tests showed mild neutropenia but normal hemoglobin; hepatic and renal function resulted within normal range. The screening for CD was negative as such as the abdomen ultrasound. Giardia lamblia was identified at the parasitological exam of stool, and metronidazole was properly administered. Gluten exclusion from diet was attempted for a short period, without any change in growth pattern. At hospital admission, the physical evaluation revealed pale and dry skin, lack of subcutaneous fat, thin and triangular face, sunken anterior fontanelle, and muscle wasting. Auxological parameters measurement revealed weight at 10^th percentile, length greater than 97^th percentile, head circumference at 90^th percentile, and a (BMI) under 3^rd percentile. At neurological examination, he showed restlessness, motor hyperactivity, and slight nystagmus. Laboratory work up confirmed mild neutropenia and showed normal hepatic and renal functionality; urine analysis and fecal occult blood test were negative. Dietetic evaluation did not identify any lack in his nutrition with appropriate nutritional daily intake. During the hospitalization, the child appeared hyperactive, kept eating with appetite, without diarrhea or vomiting. A complete hormonal assessment was normal. In the suspicion of lipodystrophy, the detection of specific Single Nucleotide Polymorphism-array, suggested by the geneticist, resulted negative. Suspecting DS, an imaging was performed: MRI documented a large multilobate pseudo-cystic suprasellar lesion (diameters 47 × 38x39 mm) showing positive widespread inhomogeneous enhancement after contrast. The mass involved asymmetrically the hypothalamic-pituitary and chiasmatic region, compressed right side of cerebral peduncles, pons, Willis’s polygon and third ventricle; lateral ventricles dimensions were moderately incremented, without leading to hydrocephalus. These results lead to the diagnosis of DS, 8 months after his weight growth begun decelerating. Histological diagnosis of pilomyxoid astrocytoma was made after biopsy. A low-grade chemotherapy regimen was started with cisplatin and etoposide. This patient is still alive and actively followed up at the time of this report. After 3 years of therapy, the lesion size remains substantially unchanged. He has developed early puberty, which is on hormonal treatment. The weight curve changed from negative to positive after nearly 6 months. One year later, his BMI Z-score was—2.94 (from—5 at the diagnosis) and it continued to slowly increase until the value of 0.01 at the last follow-up, 3 years after the diagnosis.