Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights

Introduction

The TOMM7 gene, also called translocase of the outer mitochondrial membrane 7, encodes a protein with a vital role in mitochondrial function. This protein is part of the translocase of the outer membrane (TOM) complex, which is essential for transporting nuclear-encoded proteins into mitochondria [1]. TOMM7 mutations disrupt the mitochondrial protein import process, resulting in mitochondrial dysfunction that manifests as abnormal energy production and protein expression in affected cells [2,3]. TOMM7-mutant cells exhibit increased oxygen consumption, suggesting a disconnect between oxidative metabolism and adenosine triphosphate synthesis [4].

A limited number of human diseases have been associated with mutations in genes encoding the subunits of the TOM complex. Homozygous mutations in TOMM7 are related to Garg-Mishra progeroid syndrome (GMPGS), a rare genetic disorder characterized by dwarfism, facial dysmorphia, developmental delay, and macular scarring [3,5]. Affected individuals exhibit profound growth impairment. Reported cases have involved progressive postnatal growth retardation, where body height ranges from −4.5 to −8.2 standard deviation scores (SDS) below the mean, underscoring the short stature severity associated with this condition. Furthermore, some patients with TOMM7 mutations also develop moyamoya disease, a cerebrovascular disorder characterized by progressive stenosis of the internal carotid arteries and formation of fragile collateral vessels [4]. This condition aligns with findings in animal models, in which TOMM7 deficiency leads to both mitochondrial abnormalities and cerebrovascular defects [6].

Thus far, few therapeutic interventions have been documented for conditions associated with TOMM7 mutations. Here, we present a Han boy from China with severe growth retardation who carries a homozygous TOMM7 mutation (p.Pro29Leu), inherited from consanguineous parents. Growth hormone therapy promoted further increases in height, indicating that this treatment could potentially alleviate the growth retardation caused by TOMM7 deficiency. To our knowledge, this report describes the first application of growth hormone therapy in a patient with a TOMM7 mutation, providing an opportunity to evaluate its potential as a treatment strategy.

Case Report

A Han Chinese boy first visited the clinic at 31 months of age for treatment of severe growth retardation that had persisted for at least 25 months (Figure 1A). He was born through a normal full-term delivery to consanguineous parents and had no congenital deformities. He was the second child, with 1 sibling – a 7-year-old brother who showed no clinical manifestations of growth retardation. At birth, he weighed 3,200 g (25th–50th percentile) and measured 50 cm (50th–75th percentile); he had no evident congenital anomalies. There was no prior medical history and no record of medications. His mother had exhibited good health throughout the pregnancy.

The child experienced substantial delays in length and weight beginning at 6 months of age (Figure 1B, Table 1), which prompted close monitoring and intervention at the primary hospital. During this period, his parents received comprehensive guidance regarding his nutrition and diet, including specific recommendations to increase energy intake for healthy growth. Despite these efforts and individualized dietary strategies, there was no meaningful improvement in his growth trajectory. By 24 months, he exhibited stagnation in length and weight gain (Figure 1B), but his head circumference remained normal (Figure 1C). These observations led to concerns about the underlying factors contributing to his lack of progress and triggered a thorough evaluation of his overall health and nutrition.

The patient displayed several additional clinical features, including broad hands with a distinctive shape and small, dystrophic nails (Figure 1D). He also exhibited nystagmus and muscle hypotonia, which affected mobility and coordination. Ophthalmologic examination revealed bilateral congenital macular defects and amblyopia in both eyes. His mental development showed slight delays in motor and language skills. Neurodevelopmental assessment at 27 months of age, conducted using the Griffiths Developmental Scale-Chinese version, revealed mild global developmental delay in gross motor, personal-social, auditory-linguistic, and visual-expressive domains (at the 7.5th percentile). However, there was no evidence of the distinctive facial features identified in previous cases, including low-set and protruding ears, a beaked nose, and micrognathia. The patient’s head circumference remained at approximately the 25th percentile for age.

Whole-exome sequencing revealed that the child carried a homozygous TOMM7 gene variant (NM_019059.5: Exon 1: c.86C>T [p.Pro29Leu]), inherited from both parents. Post hoc re-evaluation using American College of Medical Genetics and Genomics guidelines classified this variant as “likely pathogenic” (PS3 + PM2_Supporting + PM3_Supporting). DNA from the patient and his parents was isolated and subjected to Sanger sequencing to confirm the mutation (Figure 1E). The results demonstrated that both parents were heterozygous for the mutation. Further sequencing revealed that the patient’s sibling did not inherit this genetic variant.

Laboratory tests, including complete blood count; hepatic and renal function; and serum levels of sodium, potassium, chloride, calcium, phosphorus, magnesium, urea, creatinine, total protein, albumin, globulin, bilirubin, lipids, 25-hydroxyvitamin D, tumor markers, and allergens, all showed results within normal limits. However, slightly elevated serum levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) were observed (Table 2). Endocrine evaluation revealed normal thyroid function, adrenocorticotropic hormone, cortisol, and sex hormone levels. The serum level of insulin-like growth factor 1 (IGF-1) was at the lower limit of the normal range. A growth hormone stimulation test indicated partial growth hormone deficiency.

X-ray imaging revealed anterior vertebral beaking, resembling mucopolysaccharide-related bony changes in the spine (Figure 1F). Cardiac ultrasound showed mild regurgitation of the bicuspid and tricuspid valves. Ultrasound examinations of the liver, biliary system, pancreas, spleen, kidneys, adrenal glands, and retroperitoneum revealed no clinically significant abnormalities. Bone age, assessed at 2 years and 2 months, showed results consistent with chronological age (Figure 1G). Brain magnetic resonance imaging revealed no signs of ischemia or hemorrhage. Magnetic resonance arteriography was not performed (Figure 1H).

Because the growth hormone stimulation test indicated partial growth hormone deficiency, long-acting recombinant human growth hormone (hGH, Jintrolong®) therapy was initiated at 31 months of age. The initial dosage was 1.5 mg once weekly (0.16 mg·kg−1·wk−1). After 3 months of therapy, the dose was increased to 1.8 mg/week (0.18 mg·kg−1·wk−1); it was titrated up to a maintenance dose of 2.0 mg/week (0.20 mg·kg−1·wk−1) after 7 months, which has since been maintained. After 10 months of treatment, the child’s growth showed improvement. His length increased to 82.0 cm (an increase of 3.8 cm, with a change in standard deviation score [ΔSDS] of −0.34), and his weight reached 10.4 kg (an increase of 1.1 kg, ΔSDS of +0.26). This modest decline in length SDS sharply contrasted with the precipitous drop of 1.28 SDS (from −2.77 to −4.05) observed during the 10-month period before treatment and represented substantial improvement from the near-complete growth arrest documented between 24 and 31 months of age (Table 1). The positive change in weight SDS further underscored the overall benefit of the therapy. Serum IGF-1 increased from 76.4 ng/mL to 161 ng/mL, and IGF-binding protein-3 (BP3) reached 4126 ng/mL. Blood tests for glucose, glycosylated hemoglobin, insulin, liver and renal function, lipids, and electrolytes revealed no abnormalities (Table 2).

Discussion

We have described a boy with a homozygous missense mutation in TOMM7 (p.Pro29Leu) inherited from consanguineous parents. He exhibited normal growth parameters at birth but developed substantial growth delay beginning at 6 months of age, followed by stagnation at 2 years of age, mild developmental delays, fundoscopic macular defects, and specific skeletal changes. We found that growth hormone therapy may serve as a potential treatment to improve growth retardation. To our knowledge, this is the first report concerning the use of growth hormone therapy in a patient with a homozygous TOMM7 mutation.

TOMM7 encodes a subunit of the translocase of the outer mitochondrial membrane. The TOMM7 protein regulates the assembly and stability of the translocase complex. Few cases of TOMM7 gene mutations have been reported because symptoms require a homozygous mutation; heterozygous individuals only carry the variant and exhibit no abnormal clinical features. To date, only 12 cases of TOMM7 mutations have been documented, including 2 pathogenic missense variants (c.73T>C, p.Trp25Arg [5]; c.86C>T, p.Pro29Leu [3]) and a biallelic splicing variant (c.153-2A>C [7]). Short stature and developmental delay are the most common symptoms associated with TOMM7 deficiency caused by hypomorphic variants such as c.73T>C, p.Trp25Arg [5]. Biallelic loss-of-function variants that disrupt TOMM complex activity cause severe mitochondrial dysfunction and result in early-onset Leigh syndrome [7]. Among the 12 reported cases, 1 involved a man of Chinese descent living in Malaysia, 9 were Taiwanese, and the remaining 2 were from Japan and India. Our report involves a boy from a Han Chinese family with the TOMM7 p.Pro29Leu variant; all known patients have been of Asian ancestry. This TOMM7 variant also shows considerably higher allele frequency in East Asian populations (0.000652, 12/18 394 alleles) compared with the global aggregate (0.000048, 12/251 470 alleles) in the Genome Aggregation Database (gnomAD). Potential ethnic variance in GMPGS incidence requires further investigation.

Growth hormone is a peptide hormone secreted by the anterior lobe of the pituitary gland. It acts on nearly all body tissues, including bone, to promote growth in children. Recombinant hGH therapy treats short stature caused by several medical conditions, including growth hormone deficiency or insufficiency; birth small for gestational age; Prader-Willi syndrome [8]; Turner syndrome [9]; Noonan syndrome [10]; and other rare genetic disorders. In our patient, various interventions were attempted, including a high-calorie diet, appetite enhancement, regulation of activity and rest patterns, and structured exercise. These approaches did not result in improvement. The child experienced severe growth arrest for 8 months before initiation of hGH therapy, accompanied by a period of weight loss. Growth hormone stimulation testing revealed partial growth hormone deficiency, and no contraindications to hGH treatment were identified [11]. After initiation of growth hormone therapy at 31 months of age, the patient showed improved growth. His length increased, and his weight demonstrated a positive trend. Serum IGF-1 and IGF-BP3 levels also increased after hGH therapy began. No adverse reactions were observed during the treatment period. Notably, the previously elevated serum LDH and CK-MB levels – also observed by Young et al [5] in a patient with TOMM7 mutation – returned to normal in our patient. This improvement may be related to findings by Lakehal et al, who reported that growth hormone administration increases the oxidative capacity of red-type skeletal muscle [12], and by Nylander et al, who reported that growth hormone restores mitochondrial function and cellular membrane integrity [13].

Compared with other genetic syndromes, the growth response observed in our patient appears less pronounced than the typical first-year response to recombinant hGH treatment in Turner syndrome (0.54–0.58 SDS) or Prader-Willi syndrome (0.79–0.94 SDS) [14]. Although the absolute length ΔSDS improvement in the present case was modest (−0.34 over 10 months), this result must be interpreted in the context of the patient’s severe pretreatment growth failure, which involved a decline of −4.11 SDS after birth and near-complete growth arrest from 24 to 31 months of age. The reversal from rapid deterioration to modest improvement represents a meaningful clinical achievement. The positive weight ΔSDS (+0.26) further underscores the overall anabolic benefit of the therapy. Importantly, the follow-up duration in this study was limited to 10 months. Further longitudinal studies are warranted to evaluate long-term efficacy, safety, and the potential impact on developmental trajectories and disease progression. In addition to growth hormone therapy, patients may benefit from a supplement regimen designed to support mitochondrial function, which warrants further investigation. Such a regimen could include coenzyme Q10, B vitamins, L-carnitine, and α-lipoic acid to enhance oxidative phosphorylation, antioxidant defense, and mitochondrial biogenesis [15].

Conclusions

We have described a 2-year-old boy with a homozygous mutation in the TOMM7 gene (NM_019059.5: Exon 1: c.86C>T [p.Pro29Leu]) who exhibited severe stunted physical growth. After administration of hGH, he resumed growth in both length and weight. These preliminary findings suggest that hGH treatment can improve growth velocity at an early age in patients with TOMM7 mutations. Nevertheless, interpretation of the present findings is limited by the short follow-up duration and the single-case nature of this report. Long-term follow-up and additional case reports are essential to confirm and strengthen these findings, which may ultimately guide clinical decision-making in this rare condition.