Clinical and biochemical variation in a consanguineous family with heterozygous MAP2K2 variant and hetero/homozygous TSH receptor variant

Matthias Borschel-Thomsen; Gunter Simic-Schleicher

doi:10.1530/endoabs.110.EP820

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Endocrine Abstracts (2025) 110 EP820 | DOI: 10.1530/endoabs.110.EP820

ECEESPE2025 ePoster Presentations Growth Axis and Syndromes (132 abstracts)

Clinical and biochemical variation in a consanguineous family with heterozygous MAP2K2 variant and hetero/homozygous TSH receptor variant

Matthias Börschel-Thomsen ¹ & Gunter Simic-Schleicher ¹

Author affiliations

¹Klinikum Bremen-Nord, Bremen, Germany

JOINT2854

Introduction: MAP2K2 defects cause a cardio-facio-cutaneous syndrome (CFC) with characteristic features with high penetrance. The TSH receptor variations may cause hypo- or hyperthyroid state. Here we describe the clinical and biochemical variations of a consanguineous family where a MAP2K2 mutation (CFC4) and a TSHR mutation are encountered. Focus is given to the large clinical variation in this family and possible associations with the gene variations.

Methods and Results: The parents are 1st grade cousins with 9 children out of which 6 were examined. No typical CFC features and no heart disease were encountered apart from short stature in the mother (151,5 cm) and one of the daughters (149,2 cm). Molecular analysis of this woman showed a mutation in MAP2K2 c.464G>T; Gly135Val close to the critical position 134. It was initially judged as relevant but later as VUS. Also, a TSHR mutation was found (c.202C>T; Pro68 Ser) which was judged as VUS. Nobody had a mental or a somatic developmental delay apart from a boy with GH deficiency and delay of puberty. Height was reduced in 2/6 (< = 1 perc) but normal in 3/6 (24 – 58 perc). One patient has a GH deficiency (before GH 7 perc., near final height 20 perc). Central hypothyroidism was found in 3/4 examined patients, in all of them TSHR variation - homozygous (2/2) or heterozygous (1/1). 2/2 examined had a subtle hypoadrenalism (1 homo-, 1 heterozygous for TSHR).


	daughter son	daughter	daughter	mother	father
Age	8 1/3	17 1/3	20 1/6	25 1/2	43	47
MAP2K2	+	+	+	+	+	-
TSHR	-/-	+/+	+/+	+/-	+/-	+/-
hypothyr.	-	+	+	+	n.e.	n.e.
hypocort	n.e.	+/n. substit.	n.e.	+/n. substit.	n.e.	n.e.
GH def.	n.e.	+ (< 5,69)	n.e.	-	n.e.	n.e.
Δ bone age	0	-1,5	0	0	n.e.	n.e.
height perc.	58	20	24	<1	1	20

Discussion: There are no association with this MAP2K2 variant and height. The preponderance of neuroendocrine dysfunctions as central hypothyroidism is present. Hypothyroidism is also linked to the TSHR variant but primary hypothyroidism is expected rendering this link irrelevant. The lack of clear clinical associations to the MAP2K2 variant supports the view as allelic variant. Due to the subtle neuroendocrine dysfunctions a mild pathogenic role cannot completely ruled out.