Young-Simpson Syndrome: Further Delineation of aDistinct Syndrome With Congenital Hypothyroidism,Congenital Heart Defects, Facial Dysmorphism, andMental Retardation

Mitsuo Masuno,1* Kiyoshi Imaizumi,1 Toshihisa Okada,2 Masanori Adachi,2 Gen Nishimura,3Takuma Ishii,1 Katsuhiko Tachibana,2 and Yoshikazu Kuroki1

1Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan2Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Yokohama, Japan3Department of Radiology, Dokkyo University School of Medicine, Tochigi, Japan

Young-Simpson syndrome is a rare congen-ital disorder, characterized by congenitalhypothyroidism, congenital heart defects,facial dysmorphism, cryptorchidism inmales, hypotonia, mental retardation, andpostnatal growth retardation. We describethe cases of a 5-year-old boy and a 7-year-oldgirl with a similar constellation of symp-toms and compared them with previouslyreported patients. Am. J. Med. Genet. 84:8–11, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: Young-Simpson syndrome;hypothyroidism; facial dys-morphism; mental retarda-tion

INTRODUCTION

Young and Simpson [1987] described a girl with con-genital heart defects, hypothyroidism, mental retarda-tion, and facial dysmorphism, including blepharophi-mosis. Four additional patients with similar symptomshave been reported [Fryns and Moerman, 1988; Caval-canti, 1989; Bonthron et al., 1993; Nakamura andNoma, 1997]. We report the cases of two additionalunrelated Japanese patients with strikingly similarclinical manifestations of Young-Simpson syndromeand propose that it be recognized as a clinically distinctmalformation syndrome.

CLINICAL REPORTSPatient 1

Patient 1 is the second male child of a 37-year-oldgravida 4, para 2 mother and a non-consanguineous43-year-old father. The first and second pregnanciesended in a stillbirth of a male fetus and a hydatidiformmole, respectively, and the third resulted in a healthymale infant. The fourth pregnancy was complicated bythreatened abortion late in the second trimester. Thepatient was born at 38 weeks’ gestation after an un-eventful labor and delivery, except for polyhydramnios.The Apgar score was 8 at 1 min. At birth, the patientweighed 2,800 g (−1.0 SD), his length was 50.0 cm (+0.2SD), and his head circumference (OFC) was 36.0 cm(+1.8 SD). Tube feeding was required for 16 monthsowing to poor sucking.

He was first evaluated by us at age 3 months becauseof failure to thrive. His weight was 3,814 g (−3.8 SD),his length measured 54.7 cm (−2.9 SD), and his OFCwas 40.2 cm (−0.2 SD). He had decreased muscle tone.He also had a sloping forehead, prominent occiput,blepharophimosis, left nasolacrimal duct stenosis, bul-bous nose, low-set ears with prominent anthelix, pre-auricular pits, micrognathia, submucosal cleft palate,soft subglossal tumor, diastasis recti, bilateral cryptor-chidism, and hypermobile joints of the elbows andknees (Fig. 1a,b). Malformation of the hands and feetincluded finger-like thumbs, clinodactyly of the fifthfingers, flexion contractures of the metacarpo-phalangeal joints of all fingers, hypermobility of thedistal and proximal interphalangeal joints of all fin-gers, additional flexion creases of the third, fourth, andfifth fingers, flexion contractures of the metatarso-phalangeal joints of all toes, extension contractures ofthe proximal interphalangeal joints of all toes exceptfor the great toes, fibular deviation of the second toes,and tibial deviation of the fourth and fifth toes.

The patient had stridor and had been hospitalizedtwice for bronchopneumonia in infancy. He lifted hishead at age 9 months and sat unaided at 17 months.His developmental quotient was 37 at 3 years, 11

Contract grant sponsor: The Ministry of Health and Welfare ofJapan (a grant for Research on Mental Retardation).

*Correspondence to: Mitsuo Masuno, M.D., Division of MedicalGenetics, Kanagawa Children’s Medical Center, 2-138-4Mutsukawa, Minami-ku, Yokohama 232-8555, Japan.

Received 6 April 1998; Accepted 21 December 1998.

American Journal of Medical Genetics 84:8–11 (1999)

© 1999 Wiley-Liss, Inc.

months. He walked alone at 5 years. He spoke nomeaningful words. Thoracolumbar scoliosis had stead-ily progressed from age 4 years. Epileptic seizures alsobegan at age 4 years. An electroencephalogram showeddiffuse spike and wave bursts on both awake anddrowsy sleep records. At age 5 years, 6 months, hisweight was 16.5 kg (−0.9 SD), his height measured107.6 cm (−0.5 SD), and his OFC was 52.8 cm (+0.9SD). These values demonstrated remarkable catch-upgrowth.

An elevated thyroid-stimulating hormone (TSH)level of 210 mU/L (210 mIU/ml) was detected by driedfilter paper analysis on neonatal screening. At age 3months, he was euthyroid, and the TSH response tothyrotrophin-releasing hormone (TRH) was normal. Adiagnosis of transient hyperthyrotrophinemia wasmade. At age 2 years, thyroid function studies disclosedthe following values: thyroxine (T4), 118.4 nmol/L (9.2mg/dl); triiodothyronine (T3), 1.8 nmol/L (1.2 ng/ml);free T4, 19.6 pmol/L (1.52 ng/dl); and TSH, 5.22 mU/L(5.22 mIU/ml). The maximum TSH value attained byTRH stimulation testing was 40.7 mU/L (40.7 mIU/ml).The iodine 123 uptake was 31.5% at 24 h (normal, 10–40%). A hypoplastic right thyroid lobe and a normal-sized left lobe were found on ultrasound examination.Based on these findings, a diagnosis of mild congenitalhypothyroidism was made, and treatment with L-thyroxine was initiated. Cardiac evaluations showed aperimembranous ventricular septal defect that sponta-neously closed at age 4 years and an atrial septal defect(ostium secundum defect).

Magnetic resonance imaging (MRI) of the boy’s brainat age 5 years demonstrated homogeneous areas of T1and T2 prolongation with dilated perivascular spacesin the peritrigonal regions (Fig. 2a). These findingswere too pronounced to be comparable to the normalzones of T2 prolongation in the peritrigonal regions(terminal zones). The corpus callosum appeared mildlyhypoplastic. Computed tomography of the head showednormal results. Ultrasonographic examination of theabdomen, intravenous pyelography, voiding cystogra-phy, and a systemic skeletal survey also showed nor-mal findings. Electromyography, auditory brain-stemresponse, and ophthalmological findings, includingfundi, were unremarkable. Other normal laboratorytests included serum chemistries, amino acids, lactateand pyruvate, ammonia, immunoglobulins, lymphocyteresponses to phytohemagglutinin and concanavalin A,relative counts of T-subset lymphocytes (CD3, CD4,and CD8), TORCH serology, complete blood counts,blood gas analysis, urine organic acids, and urinalysis.He had normal chromosomes [46,XY.ish 22q11.2(TUPLE1 × 2,D22S75 × 2,D22S502 × 2)].

Patient 2

Patient 2, a girl, is the first child of healthy, non-consanguineous parents. The mother was age 28 andthe father was 33 at the time of birth. A subsequentpregnancy ended in a spontaneous abortion. The pa-tient was born at 40 weeks’ gestation by cesarean sec-tion because of cephalopelvic disproportion. The Apgarscore was 7 at 1 min. Her birth weight was 2,785 g

Fig. 1. Front and lateral views of patient 1 at age 2 years (a,b) andpatient 2 at age 7 years (c). Note bulbous nose, micrognathia, and friendlyappearance.

Young-Simpson Syndrome 9

(−0.8 SD), her length measured 48.3 cm (−0.3 SD), andher OFC was 34.5 cm (+1.1 SD). Ten min after birth,she had an apneic episode. Computed tomography ofthe head showed mild subdural hemorrhage in the ten-torium. She exhibited poor sucking, stridor, and ahoarse voice. She was first evaluated at age 27 daysbecause of an elevated TSH level of 60.5 mU/L (60.5mIU/ml), detected by neonatal screening. Her muscletone was decreased. She had a sloping forehead, promi-nent occiput, blepharophimosis, exotropia of the lefteye, bulbous nose, low-set ears, pre-auricular pits, mi-crognathia, hypermobile joints of the elbows, clinodac-tyly of the fifth fingers, and a left palmar single trans-verse crease (Fig. 1c).

At 28 days, thyroid function studies disclosed thefollowing values: T4, 106.8 nmol/L (8.3 mg/dl); T3, 2.5nmol/L (1.6 ng/ml); free T4, 15.3 pmol/L (1.19 ng/dl);and TSH, 55.0 mU/L (55.0 mIU/ml). The maximumTSH value attained by TRH stimulation test was 204.4mU/L (204.4 mIU/ml). Based on these findings, a diag-nosis of congenital hypothyroidism was made, andtreatment with L-thyroxine was initiated. At 15months of age, the uptake of iodine 123 after short-term cessation of L-thyroxine was 14.5% at 24 hr. Thebasal and maximum TSH values attained by TRHstimulation test were 4.3 mU/L (4.3 mIU/ml) and 57.4mU/L (57.4 mIU/ml), respectively.

The patient lifted her head at age 12 months and satunaided at 20 months. Her developmental quotientwas 20 at 2 years, 8 months. She walked alone at 4years, 6 months. At 7 years, her weight was 21.8 kg(−0.3 SD), her height measured 109.5 cm (−2.2 SD),and her OFC was 50.0 cm (−1.1 SD). She spoke nomeaningful words.

At age 7 years, brain MRI showed multiple patchyareas of T1 and T2 prolongation in the deep whitematter (Fig. 2b). Computed tomography of the head,cardiac evaluations, electromyography, auditory brain-stem response, electroencephalography, and ophthal-mological findings, including fundi, were unremark-able. She had normal chromosomes [46,XX.ish22q11.2(TUPLE1 × 2)].

DISCUSSIONYoung-Simpson syndrome is a rare malformation

syndrome characterized by postnatal growth retarda-tion, hypotonia, psychomotor development delay, con-genital hypothyroidism, congenital heart defects,cryptorchidism in males, and facial dysmorphism, in-cluding sloping forehead, prominent occiput, blepharo-phimosis, bulbous nose, low-set ears with prominentanthelix, and micrognathia. Congenital heart defectsinclude ventricular septal defects, secundum typeatrial septal defects, atrioventricular canal, and patentductus arteriosus. Occasionally, microcephaly, cleftpalate, pre-auricular pits, simian creases, 11 pairs ofribs, and a predisposition to infection are found [Youngand Simpson, 1987; Fryns and Moerman, 1988; Caval-canti, 1989; Bonthron et al., 1993; Nakamura andNoma, 1997].

Table I shows the clinical features of patients withYoung-Simpson syndrome. Hypothyroidism was foundin all seven patients. Although hypothyroidism wasmild in both cases presented here, the thyroid glandwas absent at necropsy in the patient described byFryns and Moerman [1988]. The origin of congenitalhypothyroidism in this syndrome may be aplasia orhypoplasia of the thyroid gland.

Brain abnormalities in this syndrome have been re-ported in one patient who demonstrated enlargementof the aqueduct of Sylvius and the fourth ventricle atautopsy [Fryns and Moerman, 1988]. Both of our pa-tients showed abnormal signal intensities in the deepwhite matter. It is not known whether the MRI find-ings represent a malformation or a nonsyndromic my-elination delay and/or white matter injury stemmingfrom perinatal asphyxia. Brain MRI is recommended,

Fig. 2. MRI findings of the patients. Patient 1 (a): homogeneous lesionsin the peritrigonal regions, which have a high signal intensity on a T2-weighted image. Patient 2 (b): multiple patchy lesions on subcortical whitematter with a high signal intensity on a T2-weighted image.

10 Masuno et al.

to elucidate abnormalities of the central nervous sys-tem in this syndrome.

Autosomal recessive inheritance of Young-Simpsonsyndrome has been proposed because of the descriptionof one affected offspring of a consanguineous mating[Bonthron et al., 1993]. However, all seven reportedpatients, including these two, were sporadic cases. Au-tosomal dominant inheritance with new mutation can-not be excluded as a possible cause. Descriptions ofadditional cases are needed to resolve the Mendelianinheritance pattern in this condition.

ACKNOWLEDGMENTS

We are grateful to Dr. S. Halford (Institute of ChildHealth, London, UK) for generously providing the cos-mid clone D0832 (D22S502).

REFERENCES

Bonthron DT, Barlow KM, Burt AM, Barr DGD. 1993. Parental consan-guinity in the blepharophimosis, heart defect, hypothyroidism, mentalretardation syndrome (Young-Simpson syndrome). J. Med Genet 30:255–256.

Cavalcanti DP. 1989. Unknown syndrome: abnormal facies, hypothyroid-ism, postaxial polydactyly, and severe retardation: a third patient. JMed Genet 26:785–786.

Fryns JP, Moerman P. 1988. Unknown syndrome: abnormal facies, hypo-thyroidism, and severe retardation: a second patient. J Med Genet25:498–499.

Nakamura T, Noma S. 1997. A Japanese boy with Young-Simpson syn-drome. Acta Paediatr Jpn 39:472–474.

Young ID, Simpson K. 1987. Unknown syndrome: abnormal facies, con-genital heart defects, hypothyroidism, and severe retardation. J MedGenet 24:715–716.

TABLE I. Clinical Comparison Between Present and Previously Reported Cases of Young-Simpson Syndrome

Patient

Reported casesa Present cases

Total1 2 3 4 5 1 2

Sex F M M F M M F 3F/4MBirth weight (g) 2,970 2,600 2,520 4,120 2,868 2,800 2,785 2,952Gestational age (weeks) 41 42 38 41 40 38 40 40Paternal age (years) 29 34 35 31 28 43 33 33.3Maternal age (years) 24 32 33 21 24 37 28 28.4Hydramnios + + − 2/3Asphyxia + + + + + − + 6/7Hypotonia + + + + + 5/5Mental retardation + NDb + + + + + 6/6Growth retardation + NDb + + + + + 6/6Hypothyroidism + + + + + + + 7/7Facial dysmorphism + + + + + + + 7/7Congenital heart defects + − − + + + − 4/7Cryptorchidism + + + + 4/4Brain abnormalities − + − − − + + 3/7

aCase 1, Young and Simpson, 1987; Case 2, Fryns and Moerman, 1988; Case 3, Cavalcanti, 1989; Case 4, Bonthron et al., 1993; Case 5, Nakamura andNoma, 1997.bND, death at 12 hr after birth.

Young-Simpson Syndrome 11