Based on our data, the clinical picture of endemic cretinism results from the product of two pathophysiological events. Both events share a common feature, namely iodine deficiency, but act at different points in time. The first event occurs in all cretins and represents the prenatal action of thyroid hormone deficiency on brain development, transmitted vertically from mother to fetus, resulting in the neurological disorder of endemic cretinism. A consistent pattern and intensity of neurological, intellectual, and audiometric deficit is common to and equally present in all types of endemic cretin. The nature of these deficits points to an intrauterine insult to the developing fetal nervous system around the time of the midtrimester. The second event represents the postnatal action of thyroid hormone deficiency on somatic as well as brain development. Whereas previous workers had attributed the differences in the clinical presentation of endemic cretinism to the presence or absence of neurological features (i.e. prenatal hypothyroidism), the distinction between the types of endemic cretin can be related to the length and severity of postnatal thyroid hormone deficiency. Endemic cretins with predominant neurological features have had only transient hypothyroidism in the postnatal period, evidenced by their near normal thyroid function and by a lack of hypothyroid clinical features. By contrast, cretins with marked myxedematous features were characterized by permanent and severe postnatal thyroid hormone deficiency. These cretins, in addition to signs of neurological damage, were typically dwarfed, sexually immature, with marked clinical features of myxedema. This second event, influenced by the thyroid gland's morphologic response to its environment (goiter or thyroid atrophy), dictates the final clinical outcome. In conclusion, our hypothesis states that the clinical expression of endemic cretinism is determined by the sum of two pathophysiologic processes. The first process is fetal hypothyroidism which results in the neurological damage of the disorder and the second process is the duration and magnitude of postnatal hypothyroidism which dictates the final clinical appearance.

Summary Background Oral propranolol is widely prescribed as first‐line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. Objectives The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. Methods Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. Results The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg−1 per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg−1 vs. 2 mg kg−1 vs. > 2 mg kg−1, the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33–1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04–5·46, P = 0·04, Ptrend < 0·001. Conclusions The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Endemic cretinism occurs in areas of severe iodine deficiency and is manifested by two major clinical patterns, myxedematous and neurological. The relationship between these types and the factors responsible for the clinical variability are not clear. We examined 69 endemic cretins, aged 4-52 yr, categorized clinically at the beginning of the study into the three traditional types of endemic cretins, myxedematous (n = 25), neurological (n = 15), and the mixed form (n = 29), from a previously unreported endemia in Qinghai Province, China. These patients underwent detailed endocrine and neurological examination, including intelligence assessment using the Hiskey-Nebraska Test of Learning Aptitude or the Griffiths Mental Development Scales, audiometry (in a subset of 37 patients); thyroid function testing and thyroid ultrasonography; and radiology of the skull, hand, and hip. We found that categorization of the cretins into the conventional types did not reflect the pathophysiology of the condition, since an identical pattern and intensity of neurological, intellectual, and audiometric deficits were common to and equally present in all three types of endemic cretins regardless of their thyroid function. Gait disorder (in 99%) and pyramidal signs such as patellar hyper-reflexia (in 91%) were the most common neurological abnormalities. There was no difference in mean intelligence test scores among the three groups [overall mean intelligence score (Hiskey or Griffiths tests), 28.8 +/- 12.8 (SD)]. The differing clinical manifestations of cretinism could be explained by the length and severity of thyroid hormone deficiency. Myxedematous cretins were severely thyroid hormone deficient, and as a result sexually immature, dwarfed, and had retarded skeletal maturity. They had clinical and sonographic thyroid atrophy, rather than goiter. Although neurological cretins were euthyroid, linear growth arrest lines (demonstrated radiologically) in the long bones of these cretins suggested previous hypothyroidism. Furthermore, all cretins were growth retarded when compared with peers of similar age and race. Our data therefore suggest that the different clinical types of endemic cretinism are in fact the same disorder phenotypically modified by the length and severity of postnatal hypothyroidism. The neurological manifestations are interpreted as reflecting the effects of maternal and fetal hypothyroxinemia, secondary to severe iodine deficiency, on the developing nervous system.