European Review for Medical and Pharmacological Sciences

2020; 24: 11998-12000

Low-birth-weight infant with Antley-Bixler
syndrome-like phenotype caused by POR mutation:a rare case report
Dear Editor,

Antley-Bixler syndrome (ABS) is a rare congenital disorder in which patients present with specificfacial features and skeletal dysplasia1. A subgroup of patients with ABS-like phenotype (Antley-Bixler syndrome type 2) exhibit abnormal external congenital anomalies and steroid production disorder2. Recently, it has been found that the cause of these features is a loss-of-function mutation inthe P450 oxidoreductase (POR) gene3, which has significantly changed the disease concept. Herein,
we report the case of an infant with ABS-like phenotype with extremely low birth weight who wasdiagnosed based on POR genetic analysis results.
The patient was the second girl of a pair of twins born via cesarean section at 34 weeks of gestation. She was admitted to our neonatal intensive care unit. The girl had intrauterine growth retardation with a birth weight of 1,018 g, and 1- and 5-min Apgar scores of 1 and 6 points, respectively. Her
mother did not show any signs of virilization during pregnancy. Post-delivery, the coronal sutures on
the patient’s forehead were fused. The shape of her cranial skull exhibited a diamond shape because
of increased head circumference with a small jaw. Hypoplasia was observed in the center of her face.
In both the ears, closure of the ear canal, hypoplasia, and accessory ears were observed. Regarding
the limbs, the humerus was fused; the patient exhibited spider-like fingers, and the second toes ofboth the feet were long. The vulva showed an enlarged clitoris and fusion of the labia minora. Inaddition, multiple joint contractures were observed (Figure 1). Postnatal blood examination did notshow any notable abnormalities. Considering the low birth weight of the neonate, an endocrinological examination was performed; it revealed that 17-hydroxyprogesterone (17-OHP), cortisol, andadrenocorticotropic levels were all within the normal range. No abnormalities were detected on mass
screening of inborn errors specific to the metabolism of the Japanese. The G-banding chromosome
analysis revealed a normal female karyotype. The patient’s clinical course often necessitated respiratory management with nasal continuous positive airway pressure because of respiratory disorders
caused by the stenosis of the entire nasal cavity and subsidence of the tongue base. Oral intake wasdifficult because of micrognathia; thus, tube feeding was performed. Moreover, there were no signsof adrenal insufficiency, such as hypoglycemia, electrolyte abnormalities, and decreased blood pressure; therefore, no corticosteroid supplement was required at that time.
We suspected ABS on the basis of gross external malformations in the infant. We performed aurine steroid profile analysis and genetic testing after obtaining informed consent from the infant’s
parents. The urine steroid profile analysis revealed high levels of some urinary metabolites including
pregnenolone, progesterone, 17-OHP, and 21-deoxycortisol. Conversely, dehydroepiandrosterone,androstenedione, and 11b-hydroxyandrostenedione levels were decreased; these results suggested
a decreased activity of several P450 enzymes.
The genetic testing was focused on the POR gene. An analysis of the POR gene exons showeda guanine-to-adenine substitution in exon 11. Based on this base substitution, a missense mutation(R457H) in which the arginine at position 457 was replaced by histidine that was identified heterozygously; no R457H mutation was detected in the other allele (Figure 2).

Later, at 3 months after birth, the child was transferred to another general hospital. Afew days later, she developed a fever and a blood test was performed, revealing the presence of marked hyponatremia (118 mEq/L). Since clinical adrenal insufficiency could not beruled out, electrolyte replacement by infusion and corticosteroid replacement were per11998

Corresponding Author: George Imataka MD., Ph.D., B.Phil., LL.B., PGDBA;
e-mail: geo@dokkyomed.ac.jp

Letter to the Editor

Figure 1. General appearance of the congenital external abnormalities of the patient. A/B, Diamond-shaped cranial skull anomaly caused by an increase in the circumference of the head and presence of a small jaw. C, A fusion anomaly of the humerus
and joint contracture of the elbow were recognized in the left upper arm. D, Spider-like finger malformations. E, Long toes. F,Genital fusion abnormality.

Figure 2. Genetic testing for the POR gene.

formed. First, as an initial treatment, hydrocortisone was intravenously injected at 10 mg/kg. Next, hydrocortisone was intravenously injected at 15 mg/kg/day in three divided doses
over 2 days. Thereafter, her hyponatremia promptly improved. Currently, approximately
7 months after birth, she does not need corticosteroid supplementation, and her generalcondition is stable.
Herein, we reported a case of ABC-like phenotype, a rare autosomal recessive congenital malformation syndrome. ABS syndrome is characterized by early skull fusion, boneand joint symptoms in the limbs, and abnormalities in the external genitalia. According11999

G. Imataka, M. Fujisawa, R. Kuribayashi, G. Ichikawa, Y. Watabe, H. Suzumura, et al

to the causative gene-based classification, the type of ABS in which patients present withsteroid production disorder and external genital abnormalities, i.e., ABS-like phenotype
presence, is considered to be caused by POR gene mutation, whereas the type in which
patients do not exhibit the above presentations is considered to be caused by FGFR2 genemutation4,5; i.e., ABS and POR disorder (PORD) clinically overlap. The major cause of PORD
is the loss of multiple POR-dependent enzyme activities because of POR gene loss-of-function mutations6. Therefore, the symptoms of bone dysgenesis, complex adrenal steroid
profile production, and external genital abnormalities observed in the present case ofABS were deemed symptoms of PORD-overlapping ABS. In the treatment of PORD, respiratory management is critical in the neonatal period and hormone replacement therapy
and rehabilitation are required during infancy. With the exception of severe cases, the lifeand intellectual prognoses range from moderate to good7 and several cases of low-birthweight infants have been reported. Occasionally, sudden death occurs in patients withPORD, possibly because of adrenal insufficiency8. Our patient also developed sudden hyponatremia associated with infection, but steroid replacement therapy promptly improved
the symptoms. Such patients may suffer from adrenal insufficiency during several typesof stress, such as infection and surgery; therefore, physicians should be aware of a risk ofmetabolic stress-like symptoms in the daily management of such ABS-like phenotype.
Acknowledgements

Thank you for analyzing and providing suggestions for the urine steroid profile (Keiko Honma, Department of Laboratory Medicine, Keio University Hospital and Tomonobu Hasegawa, Department of Pediatrics, Keio University) and POR geneanalysis (Maki Fukami and Tsutomu Ogata, Department of Molecular endocrinology, National Center for Child Health andDevelopment) of the patient.

Conflict of Interest
The Authors declare that they have no conflict of interests.

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8) Williamson L, A rlt W, Shackleton C, K elley RI, Braddock SR. Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a novel case of P450 oxidoreductase deficiency. Am J Med Genet A 2006; 140A: 1797-1803.
G. Imataka1, M. Fujisawa1, R. Kuribayashi1, G. Ichikawa1, Y. Watabe1, H. Suzumura1, O. Arisaka1,2, S. Yoshihara1
Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan2
Department of Pediatrics, Nasu Red Cross Hospital, Tochigi, Japan

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