2024年3月31日发(作者：)

出生/妊娠情况

 was the first child born to unrelated healthy parents after a full-term

pregnancy.

 The patient was born after a full-term pregnancy by caesarean section

because of premature rupture of the membranes足月、剖腹产、胎膜早破

 she spontaneously breathed and cried.

 The proposita, a 15-year-old girl, was the product of the fifth full-term

pregnancy.

 Polyhydramnios was present in the third trimester. 晚期妊娠羊水过多

 Anthropometrical data recorded at birth were: weight 1700g ( < 3rd centile)

and height 40cm ( < 3rd centile).

 He was the first child of a nonconsanguineous 非近亲结婚Turkish couple

born at term by normal spontaneous vaginal delivery. 顺产

 This 13-year-old boy was born to non-consanguineous Pakistani parents by

Caesarean section and weighed 3.6 kg (50th centile) at birth.

 She was delivered by Cesarean for failure to progress 停育at 37 weeks’

gestation.

 Pregnancy was characterized by intrauterine growth retardation宫内发育迟

缓, nuchal thickness, and turbidity of amniotic fluid requiring a caesarean birth at

the 39th week of gestation.

 short femora 股骨短

家人情况

 Her younger sister is healthy.

 A 13-year-old girl was the second child born to a 42-yearold mother and an

unrelated 43-year-old father

 There was no family history of short stature, mental deficiency or congenital

anomalies

 He is the only affected member in his pedigree

 At the time of his birth, his father was 35 year-old, 170 cm tall, his mother

was 32 year-old, 157 cm tall and obese.

 He had two brothers; one was obese but had neither learning difficulties nor

visual impairment.

生长发育

 Her developmental milestones were normal

 At 11.5 years of age, her height was 129 cm ( – 3 SD), weight 29 kg ( – 1.5

SD), and occipitofrontal circumference 49 cm ( – 2.75 SD).

 Along with her cognitive profile, she showed difficulty in mathematics,

reading and writing. 学习困难

 His height and weight have remained markedly below the 3rd percentile

 His height and weight have always been below the 3rd percentile

 Stature (115 cm, 10–25th centile) was disproportionate to the weight (30 kg,

97th centile)

 病情发现

 We call attention to

 Soon after birth, were noted.

 She attained menarche at

 The patient exhibited a full MS phenotype of the clinical and radiological

criteria reported in MS, including

 Multiple/ Several congenital anomalies were noted at birth including cleft

lip and palate唇腭裂, left facial paralysis左面部瘫痪, systolic heart murmur左面部

瘫痪, pilonidal dimple, hypospadias with meatal stricture尿道下裂, congenital

phimosis先天性包茎, right crytorchidism右隐睾 and inguinal hernia腹股沟疝.

 Hypertension was documented at age 1 1 years

 Marked hyperopia was found on an ophthalmologic examination at age 21

years

 At age 1 year he was felt to be developmentally delayed

 From infancy the mother noticed the existence of hearing-loss which

remained untreated until adolescence.

 He has hypernasal speech because of adenoid hypertrophy.

 From age 3 years he frequently refused to walk complaining of painful legs.

就诊原因

 She was referred to us for investigating her short stature at the age of 10

years

 He was admitted to a state institution for the mentally retarded at age 30

years with

 He was first referred to a pediatric nutritionist at the age of seven years for

the exploration and management of polyphagia and obesity.

 He presented to endocrine clinic at age 11 for short stature and precocious

puberty (onset at age 10), and had elevated FSH, and an enlarged left testis.

 特殊面容 Craniofacial features/ Craniofacial features

 She had a flat wide facies with prominent prognathism, blepharophimosis,

and a narrow mouth with a thin vermilion of the upper lip

 She had a short stature and an unusual square-shaped body habitus with

horizontal position of the clavicles and shoulders along with a short neck

 flat wide facies with upward slanting palpebral fissures, blepharophimosis,

and a flat nasal bridge with hypoplastic left nares and flat maxillary regions.

 She had a muscular build肌肉身材, brachycephaly短头畸形, frontal bossing

额部隆起, hypertelorism眼距过宽, a broad and prominent nasal bridge宽鼻梁, deep-

set eyes 凹眼with short palpebral fissures短睑裂, midfacial hypoplasia面中部发育

不良, small external ears小外耳, a short philtrum短人中, a narrow mouth窄嘴, a

thin upper lip上嘴唇薄, downturned corners to the mouth嘴角向下翘, hypoplastic

teeth发育不全的牙齿, a high palate高上腭, prognathism凸颚, a short neck短颈,

Tanner III breast development and external genitalia, short upper limbs 短上肢

(rhizo-acromelic shortening), cubitus valgus肘外翻, brachydactyly of the hands and

feet手脚短指, clinodactyly of the fifth fingers指过弯, generalized nail dysplasia指

甲发育不良, and normal skin and joint movements

 Facial dysmorphism indicative of Myhre syndrome included short palpebral

fissures with ptosis, a flat face with mid-face hypoplasia, prognathism and a high

arched palate

 Facial and limb morphology further suggested the diagnosis of MS

检查

 Audiological examination revealed mixed conductive and sensorial hearing

loss

 Radiological examination revealed a thick calvarium, mandibular protrusion，,

shortening of the tubular bones, and large pedicles and thick neural arches,

resulting in a narrow spinal canal.

 MRI showed thick basilar bone and large and thick clivus.

 The patient underwent a provocative test by insulin-induced hypoglycemia

(ITT), thyrotropin-releasing hormone (TRH), and luteinizing hormone-releasing

hormone (LHRH)

 Radiographic studies (Fig. 2) showed

 the peak GH response was

 the serum IGF-1 level was appropriate for a pubertal girl

 Physical findings at age 24 years (Fig. I) revealed/ showed a height of 140

cm, weight of 45 kg and a head circumference of 56 cm.

 On physical exam/ examination at age 18 years he had a height of 146 cm,

a weight of 50.5 kg and a head circumference of 54.7 cm

 The skeletal survey showed multiple abnormalities

 His muscle mass and strength werc increased 升高

 The skeletal survey demonstrated multiple skeletal ab normalities identical

to those pictiired in Case 1

 Psychological evaluation showed an IQ of 48

 A muscle biopsy revealed fascicles of normal looking muscle fibres

 Gene sequencing analysis was carried out of all 11 coding exons of SMAD4

using the MiSeq next-generation sequencing platform

 Musculoskeletal examination revealed generalised stiff muscles, limited

phalangeal extension

 Neurological examination was normal apart from clumsy gait with toe

walking.

 he was normotensive (120/65 mm Hg) 血压正常

 he had mild learning difficulties that necessitated additional educational

support. 特殊教育

 Dermatological assessment of the proband revealed keratosis pilaris with a

clinical impression of thickened skin. 皮肤病学Skin biopsy findings confirmed

 Three additional clinical genetics evaluations failed to identify a unifying

diagnosis.

 检查结果正常

 Results of the routine biochemical studies were within the normal ranges.

 Results of the screening tests for metabolic defects, including analysis of

urinary mucopolysaccharides and blood amino acids were normal.

 Routine karyotyping (G-bands) showed 46,XX, and the results of the array

CGH (Agilent SurePrint G3 60K) were also negative

 EMG showed no abnormalities.

 Endocrinological studies (basalthyroid profile,LH, FSH, estradiol, cortisol,

and IGF-1 serum determinations，thyroid profile) showed normal results.

 No signs of polycystic ovary syndrome were identified.

 The histology of a striated muscle biopsy was normal.

 Cardiovascular evaluations began at age 3 years when a twodimensional

echocardiogram showed mild valvar pulmonic stenosis, and clinical follow-up

suggested resolution

 Sequencing for Kabuki and Rubinstein–Taybi syndromes, (MLL2, CREBBP,

and EP300) was normal

 Psychomotor development was normal 智力，精神发育正常

被诊断

 She was diagnosed with

 We propose that

 The thick calvarium and thick and stiff skin were clues to the diagnosis of MS

 She fulfilled the clinical criteria reported for MS.

 This finding indicated that her GH secretion was not defective.

 Gonadotropin responses were not excessive or inappropriate for an early

pubertal girl.

治疗

 necessitating hormone replacement therapy.

 The patient was diagnosed with skeletal dysplasia of unknown origin and

treated for this condition for several years

 He required surgery for right cryptorchidism at the age of 1.5 years.

 The prednisone dose was raised (1 mg/kg/day) with a good clinical response

 mycophenolate-mofetil (500 mg twice/day) was added for two months to

the prednisone therapy.

 The starting dosage of anakinra was 1 mg/kg/day, subcutaneously. 皮下注

射

 年龄

At the age of 15,

测序

 Direct sequence analysis of the coding lesions led to the identification of

three missense mutations in the region ofSMAD4 coding for the MH2 domain

 No likely pathological copy number variants (CNVs) were detected in either

case 1 or his mother on a 180 K oligo array CGH

报道发病情况

 All cases have been sporadic and an autosomal dominant inheritance was

suggested because of advanced paternal age.

青春期

 These findings suggest that endocrinological abnormalities related to the

hypothalamus–hypophysis feedback may be part of the syndrome. This has been

proven at least in one male patient (Case 2, Burglen et al., 2003).

 the abnormal onset of puberty observed in three of our cases, two showing

early onset (before the age of 9 years) and another one showing delayed puberty

with hypergonadotrophic hypogonadism. Although these phenotypic

manifestations are discordant, they may point to a disturbance in the

hypothalamohypophyso-gonadal axis that should be investigated in further cases.

疾病

 Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-

function mutations in SMAD4

 The characteristic phenotype includes

 Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome

from other disorders caused by mutations in the TGF-b signaling cascade (Marfan,

Loeys–Dietz, or Shprintzen–Goldberg syndromes)

 Major facial features were

病例报道

 We report four newly described patients with typical features of Myhre

syndrome who had

 To our knowledge, the severely shortened distal phalanges, shortened third

metacarpals, and shortened proximal phalanges of digit 5 have not yet been

reported elsewhere as being associated with BDA1 据我们所知，在其他地方尚未报

道严重缩短远端指骨，缩短第三掌骨和缩短指骨5位与BDA1相关

不明

were not recorded