LHX3 deficiency presenting in the United States with severe developmental delay in a child of Syrian refugee parents

Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin.Epidemiology: The incidence is 1 in 4,000–1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80–90% of CH cases remain unsolved in terms of molecular genetics.Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8. Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation.Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies.Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.

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“…In humans, 14 homozygous ( 86 – 94 ) or compound heterozygous LHX3 mutations ( 10 ) and a heterozygous variant ( 95 ) have been reported to date.…”

Section: Correlation Between Phenotype-genotypementioning

confidence: 99%

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome

2021

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Hearing impairment and vestibular function in patients with a pathogenic splice variant in the LHX3 gene

Kjellgren,

Lundgren,

Golovleva

et al. 2024

BMC Med Genomics

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Background LHX3 is a gene encoding a LIM-homeodomain transcription factor important for the fetal development of several organs, such as the pituitary gland, spinal motor neurons and the inner ear. Pathogenic and likely pathogenic variants in the LHX3 gene are infrequent and result in a rare syndrome known as combined pituitary hormone deficiency-3, CPHD3. Methods We have studied hearing and vestibular functions in a group of eight individuals, aged 8–36 years, all of whom were homozygous for a specific variant in the LHX3 gene at chromosome 9q34. We reexamined the results of consecutive hearing tests from newborn until April 2024. Results Our data showed that all the tested patients had progressive sensorineural hearing deficiency ranging from moderately severe to complete loss. We have performed vestibular testing in six patients and, for the first time, demonstrated that a mutation in the LHX3 gene not only affects hearing, but is also associated with vestibular impairment. Conclusion The human pathogenic variant c.455-2A > G in the LHX3 gene on chromosome 9q34, which present as a founder mutation in the population in northern Sweden, is responsible for phenotypes associated with progressive hearing loss and balance impairment. These findings prove that the LHX3 gene is crucial for the function of both the cochlear and vestibular organs.

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Genetic Anomalies of Growth Hormone Deficiency in Pediatrics

Firouzi

Sherkatolabbasieh

Shafizadeh

2021

EMIDDT

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: Several different proteins regulate, directly or indirectly, the production of growth hormone from the pituitary gland, thereby complex genetics is involved. Defects in these genes are related to growth hormone deficiency solely, or deficiency of other hormones, secreted from the pituitary gland including growth hormone. These studies can aid clinicians to trace the pattern of the disease between the families, start early treatment and predict possible future consequences. This paper highlights some of the most common and novel genetic anomalies concerning growth hormone, which are responsible for various genetic defects in isolated growth and combined pituitary hormone deficiency disease.

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LHX3 deficiency presenting in the United States with severe developmental delay in a child of Syrian refugee parents

Cited by 3 publications

References 10 publications

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome

Hearing impairment and vestibular function in patients with a pathogenic splice variant in the LHX3 gene

Genetic Anomalies of Growth Hormone Deficiency in Pediatrics

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