Santoro Claudia, Aiello Francesca, Farina Antonella, Miraglia Del Giudice Emanuele, Pascarella Filomena, Licenziati Maria Rosaria, Improda Nicola, Piluso Giulio, Torella Annalaura, Del Vecchio Blanco Francesca, Cirillo Mario, Nigro Vincenzo, Grandone Anna
Department of Child, Woman, General and Specialized Surgery, University of Campania "L. Vanvitelli", L. De Crecchio 4 Street, 80138 Naples, Italy.
Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Sant'Andrea delle Dame Square L. De Crecchio 7 Street, 80138 Naples, Italy.
Children (Basel). 2025 Mar 14;12(3):364. doi: 10.3390/children12030364.
Multiple genes can disrupt hypothalamic-pituitary axis development, causing multiple pituitary hormone deficiencies (MPHD). Despite advances in next-generation sequencing (NGS) identifying over 30 key genes, 85% of cases remain unsolved, indicating complex genotype-phenotype correlations and variable inheritance patterns.
This study aimed to identify the MPHD genetics in three probands from two unrelated families.
Family A had one affected child, while Family B had two affected siblings. All probands exhibited poor growth since birth, and family B's probands were born small for gestational age. Growth hormone deficiency was confirmed in all subjects. Family B's probands responded poorly to growth hormone treatment compared to the first patient. Furthermore, Family A's proband and Family B's younger sibling developed central hypothyroidism, while Family B's older sibling presented hypogonadotropic hypogonadism. Brain magnetic resonance imaging (MRI) revealed pituitary hypoplasia, ectopic posterior pituitary gland, and small sella turcica in all probands. Patients and their available relatives underwent NGS.
NGS identified the same novel and likely pathogenic LHX4 variant (c.481C>G) in all probands despite the families being unrelated. Additionally, Family A's proband carried a variant (c.2105C>A), and Family B's probands carried an IGF1R variant (c.166G>A), both interpreted as being of uncertain significance.
This study confirms that heterozygous pathogenic variants of LHX4 can cause MPHD associated with a specific neuroradiological triad of abnormalities despite incomplete penetrance and variable phenotype. Moreover, the co-occurrence of the other two gene variants was debated. The variant could explain the unusually poor response to growth hormone therapy in Family B, suggesting an oligogenic mechanism underlying the phenotype.
多个基因可破坏下丘脑 - 垂体轴的发育，导致多种垂体激素缺乏症（MPHD）。尽管下一代测序（NGS）技术取得了进展，已鉴定出30多个关键基因，但85%的病例仍未得到解决，这表明存在复杂的基因型 - 表型相关性和可变的遗传模式。
本研究旨在确定来自两个无关家族的三名先证者的MPHD遗传学特征。
家族A有一名患病儿童，家族B有两名患病兄弟姐妹。所有先证者自出生以来生长发育不良，家族B的先证者出生时小于胎龄。所有受试者均确诊为生长激素缺乏症。与首例患者相比，家族B的先证者对生长激素治疗反应较差。此外，家族A的先证者和家族B的年幼兄弟姐妹发生了中枢性甲状腺功能减退，而家族B的年长兄弟姐妹表现为低促性腺激素性性腺功能减退。脑磁共振成像（MRI）显示所有先证者均有垂体发育不全、垂体后叶异位和蝶鞍较小。患者及其可及的亲属接受了NGS检测。
尽管两个家族无关，但NGS在所有先证者中均鉴定出相同的新型且可能致病的LHX4变异（c.481C>G）。此外，家族A的先证者携带一个变异（c.2105C>A），家族B的先证者携带一个IGF1R变异（c.166G>A），两者均被解释为意义不明确。
本研究证实，尽管外显不全和表型可变，但LHX4的杂合致病变异可导致与特定神经放射学三联征异常相关的MPHD。此外，对另外两个基因变异的共现情况进行了讨论。该变异可以解释家族B中对生长激素治疗异常差的反应，提示该表型存在寡基因机制。
