Lysinuric protein intolerance (LPI; OMIM #222700) is a rare autosomal recessive aminoaciduria resulting from biallelic mutations in the SLC7A7 gene. SLC7A7 is located at 14q11.2, which encodes the transporter of cationic amino acids, lysine, arginine, and ornithine, in the kidney and small intestine [1, 2]. LPI has been sporadically reported worldwide, with a higher prevalence in Finland, Southern Italy, and Japan [2,3,4]. Only one case has been reported in Korea [5]. The clinical features of LPI are extremely variable, ranging from nearly normal growth with minimal protein intolerance to severe multisystemic involvement with failure to thrive, hepatosplenomegaly, pulmonary alveolar proteinosis, renal tubulopathy, and immunologic disorders [6].

Maternal uniparental disomy 14 (UPD14mat), the most common cause of Temple syndrome (TS14, OMIM #616222), is associated with the lack of expression of paternally inherited genes in the imprinted locus 14q32.2 [7, 8]. TS14 is characterized by intrauterine growth retardation, postnatal growth failure, motor delay, Prader–Willi syndrome-like marked hypotonia and small hands and feet, Silver–Russell syndrome-like relative macrocephaly, prominent forehead and feeding difficulties in infancy, as well as early onset of puberty, and severe short final stature.

Here, we report the first case of combined LPI and TS14 with UPD14mat carrying an SLC7A7 mutation, manifesting as severe feeding intolerance, growth failure, and profoundly delayed development. The patient was naturally conceived and the second child of unrelated healthy Korean parents. The paternal age and maternal age at the time of the patient’s birth were 35- and 36-years-old, respectively. She was born at 39 weeks and 2 days of gestation with a birth weight of 2 kg (−3.72 standard deviation score [SDS]), a height of 48 cm (−2.10 SDS), and a head circumference of 33 cm (−0.70 SDS). At the age of 4 months, her parents sought medical attention for apparent failure to thrive and increased frequency of vomiting after attempts to increase caloric intake. At 11 months of age, her height was 60 cm (−4.78 SDS), weight was 4.1 kg (−5.96 SDS), and head circumference was 41 cm (−2.43 SDS). The physical examination was notable for frontal bossing, a large anterior fontanelle, thin hair, a flat nasal bridge, a protruded abdomen without organomegaly, and small hands and feet. She was hypotonic, and though she grasped her rattle and smiled in response to faces, she could not hold her head steady. Initial laboratory tests revealed normocytic anemia (hemoglobin 9.5 g/dL) and mildly elevated aspartate transaminase and alanine transaminase (95 IU/L and 46 IU/L). Serum lactate dehydrogenase (1138 IU/L) and ferritin levels (3831 ng/mL) were also elevated. Her plasma ammonia level was 57 μmol/L (reference range, 11–32). A simple X-ray revealed normal lungs with gaseous distension of the abdomen (Fig. 1a). The abdominal ultrasound demonstrated slightly heterogeneous echogenicity of the liver, without a focal lesion. Cerebral magnetic resonance imaging results showed mild myelination delay considering the patient’s age (Fig. 1b). Her karyotype was 46, XX and the methylation specific-multiplex ligation-dependent probe amplification analyses on chromosome 11p15 and 15q11.2-q13 were normal.

Fig. 1
figure 1

Radiologic findings, genetic analysis, and growth chart of the patient. a Diffuse air distension of bowel loops was observed on simple X-ray. b Brain magnetic-resonance imaging obtained at 9 months of age showed no focal lesions in the brain parenchyma and mild myelination delay. c Genetic mutational analysis showed pathogenic homozygote mutations of SLC7A7. The familial segregation study showed the heterozygous mutation only in the mother, with wild-type alleles in the father. d The analysis revealed a loss of heterozygosity spanning the entire chromosome 14. e The patient’s growth chart plotted by Korea Center for Disease Control and Prevention chart percentiles. Regardless of a low-protein diet, supplementation with citrulline and lysine, and continuous enteral feeding to improve caloric intake, the patient failed to achieve catch-up growth due to recurrent abdominal distension, vomiting, and diarrhea

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The results of plasma amino acid analysis were within normal range, except for a slightly elevated citrulline level and a decreased ornithine level. The patient’s urinary orotic acid level was 228 mmol/mol creatinine (reference range, 0.0–4.6 mmol/mol creatinine) with markedly elevated urinary excretion of arginine, citrulline, glutamine, lysine, and ornithine (Table 1). The diagnosis of LPI was confirmed by the detection of the homozygous mutation of c.713 C>T (p.Ser238Phe) in the SLC7A7 gene, which has previously been reported in Japanese patients [9]. The familial segregation study showed the heterozygous mutation only in the mother, with wild-type alleles in the father (Fig. 1c). Single-nucleotide polymorphism microarray (aSNP) was performed to detect UPD14, revealing a loss of heterozygosity encompassing the entire chromosome 14, on which the SLC7A7 gene is located (Fig. 1d). No deletions or duplications were observed. The Sanger sequencing and aSNP revealed the presence of maternal isodisomy of chromosome 14 (UPiD14mat) in our patient. Whole-exome sequencing to exclude the possibility of another genetic disorder causing developmental delay did not reveal a pathogenic, clinically relevant variant except for the SLC7A7 mutation.

Table 1 The results of plasma and urine amino acid analyses at diagnosis and during follow-up
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Soon after receiving the diagnosis of LPI, the patient started a low-protein diet (1.5 g/kg/day) with oral citrulline (100 mg/kg/day with meals) and lysine (150 mg/kg/day) supplementation. During the 3-year follow-up period, there were no episodes of acute metabolic derangement. However, inadequate caloric intake persisted through age 4 years due to recurrent flatus, abdominal distension, and vomiting after feeding. This produced severe malnutrition with a global decrease in almost all plasma essential amino acid levels (Table 1). Her weight and developmental status did not improve despite efforts to increase caloric intake, such as continuous gastric tube feeding (Fig. 1e). Her renal and pulmonary function remained normal.

The three possible mechanisms can be considered to explain UPiDmat of whole chromosome [10, 11]. The first is trisomy rescue by elimination of the paternal chromosome after fertilization by a disomic oocyte, which had a meosis II nondisjunction without meiotic recombination. Advanced maternal age is a major risk factor for chromosome nondisjunction. The second is monosomy rescue after fertilization of a sperm with nullisomy. The third is gamete complementation, which related to the fertilization of a nullisomic sperm by a disomic oocyte. We do not know the underlying mechanism of UPiDmat of our patient. However, it would be associated with advanced parental ages.

Failure to thrive and short stature are hallmarks of both LPI and TS14. Poor growth in LPI has been considered a postnatal condition caused by protein malnutrition, but a subnormal or low-normal final height is usually achieved through adequate nutritional support [12]. In addition, both intrauterine and postnatal mild to moderate growth failure are observed in most TS14 patients, but early puberty results in severe adult short stature in some cases [7, 8]. The birth height SDS and childhood height SDS of our patient were −2.10 and −6.06, respectively. The profound growth failure in our patient was caused by both TS14 and LPI, but the secondary malnutrition, manifested as recurrent abdominal distension and vomiting, and growth hormone deficiency might be responsible for her profound growth failure as well [13,14,15]. In the situation of malnutrition, the diagnosis of growth hormone deficiency may be uncertain due to reduced IGF-1 levels and variable stimulated growth hormone concentrations [16]. Therefore, growth hormone provocation testing could be considered in the future when the patient’s nutritional status improves. However, the efficacy of growth hormone would be limited due to severe malnutrition.

The gastrointestinal symptoms in LPI patients are usually associated with an acute hyperammonemic crisis. However, our patient showed persistent malabsorption with gaseous abdominal distension and vomiting without an episode of hyperammonemia. Altered arginine and nitric oxide concentrations in the enterocyte may have been responsible, because the dibasic amino acids, especially l-arginine, have a secretory effect on the enterocytes in its high concentrations [17].

Our patient presented with intrauterine growth retardation without catch-up growth after birth and showed persistent failure to thrive, hypotonia, delayed development, facial dysmorphism, and small hands and feet. Based on analysis of markedly elevated urinary excretion of dibasic amino acids, Sanger sequencing of the SLC7A7 gene, and aSNP analysis, we diagnosed LPI with UPiD14mat, which is the first case to our knowledge. In conclusion, our study underlines the importance of performing parental segregation studies, even in patients with a recessive disease and previously reported mutations, especially when the mutation is found to be homozygotic. Imprinting disorders such as UPD may underlie and contribute to the severity of the recessive disease.