Table 1 Clinical and molecular data of affected individuals affected

Sex

M

M (proband)

M (son)

F

F

F

F

M

M

M

F (proband)

M (father)

M (brother)

M (brother)

Age at last examination

10 yrs

32 yrs

8 months

13 yrs

9 yrs

4 yrs

5 yrs

23 yrs

8 yrs

Death: 40 yrs

26 yrs

Death: 56 yrs

Death: 30 yrs

31 yrs

Consanguinity

No

Yes

No

No

No

No

No

No

No

No

No

No

No

No

General

Growth retardation/Hypotrophy (height; weight)

No

165 cm (−1.7 SD); 40 kg (BMI:14.7)

No

145 cm (−1.5 SD); 30 kg (BMI: 14.3)

120 cm (−1.9 SD); 15.8 kg (BMI:11)

102 cm (+0.2 SD); 14 kg (BMI:13.5)

91.3 cm (−3.9 SD); 12.3 kg (BMI:14.8)

No

No

163 cm (−2.1 SD); 53 kg (BMI:19.9)

No

No

No

No

Delayed puberty

n/a

Yes (17 yrs)

n/a

Yes

n/a

n/a

n/a

No

n/a

No

n/a

n/a

n/a

n/a

Normal IQ

Yes

Yes

n/a

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Psychiatric disorders

No

No

n/a

No

No

No

No

No

No

Schizophrenia

No

No

No

No

Skin

Poikiloderma (early childhood)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

 - Face

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

 - Exposed area/photosentivity

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

 - Upper and/or lower limbs

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Bullous lesions

Yes

No

No

No

No

No

Yes

No

No

No

No

No

No

No

Eczema-like

Yes

Yes

Yes

No

Yes

Yes

Yes

No

No

No

No

No

No

No

Ichthyosis-like

No

No

No

No

No

Yes

No

No

No

Yes

Psoriasis-like

No

No

No

No

Yes

No

No

No

No

No

No

No

No

No

Blaschko linear hypo/hyperpigmentation

No

No

No

No

No

Yes

No

Yes

No

No

No

No

No

No

Lymphoedema of extremities

Yes

No

No

Yes

Yes

Yes

Yes

Yes

No

Yes

No

No

No

No

Cellulitis

Yes

No

No

Yes

No

No

Yes

No

No

No

No

No

No

No

Sclerosis of the digits

No

Yes

No

No

No

No

No

No

No

No

Yes

n/a

n/a

Yes

Palmoplantar abnormalities

No

No

No

No

No

Palmar erythrosis and palmoplantar keratoderma

No

No

Palmar erythrosis

Palmoplantar keratoderma

Hypohidrosis/Heat intolerance

Yes

Yes

Yes

n/a

Yes

Yes

Yes

Yes

No

n/a

Yes

Yes

Yes

Yes

Hair

Hypotrichosis/Alopecia

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

n/a

n/a

Yes

- Scalp hair

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

- Eyebrows

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

- Eyelashes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

Nails

Dysplasia

No

No

No

Yes

No

No

Yes

Yes

No

No

Yo

No

No

No

Muscle

Muscle weakness (Age at onset)

Yes (7 yrs)

Yes (11 yrs)

No

Yes (4y)

Yes (14 months)

No

Yes (infancy)

Yes (2 yrs)

Yes (8 yrs)

No

Yes (9 yrs)

n/a

n/a

n/a

 - Proximal lower limbs

Yes

yes

No

Yes

Yes

No

Yes

Yes

Yes

No

n/a

n/a

n/a

n/a

 - Distal lower limbs

Yes

Yes

No

Yes

Yes

No

No

Yes

Yes

No

n/a

n/a

n/a

n/a

 - Proximal upper limbs

Yes

Yes

No

Yes

Yes

No

No

Yes

No

No

n/a

n/a

n/a

n/a

 - Distal upper limbs

Yes

Yes

No

Yes

Yes

No

No

Yes

No

No

n/a

n/a

n/a

n/a

 - Neck: extensors/Sternocleidomastoid (SCM)

No

Yes (SCM), trunk extensors, abdominal muscles

No

n/a

Yes

No

No

Yes

No

No

n/a

n/a

n/a

n/a

Amyotrophy

Yes

Yes

No

Yes

Yes

No

No

No

No

No

n/a

n/a

n/a

n/a

Abolition of lower limb tendon reflex

No (weak reflexes)

Yes

No

Yes

Yes

No

n/a

Yes

No

No

n/a

n/a

n/a

n/a

Tendon lengthening (age)

Yes (7 yrs)

Yes (11 yrs)

No

Yes (13 yrs)

No

No

No

No

No

No

Yes (14 yrs)

No

Yes (5 yrs)

No

Joints

Lower limbs contractures(Age at onset)

Triceps surae (6 yrs)

Triceps surae (7 yrs)

No

Triceps surae

Triceps surae (2 yrs) Hamstring (7 yrs)

Triceps surae (3 yrs)

Triceps surae (4 yrs)

No

Triceps surae (7 yrs)

No

Triceps surae

n/a

n/a

No

Triceps surae muscle/Hamstring muscle

Upper limb contractures

No

Biceps brachii (2–3 yrs) Carpal extensor

No

Yes

Yes

No

No

Yes (identified at age 23)

No

No

No

n/a

n/a

No

Biceps brachii and carpal extensors

Spine

Scoliosis

No

Yes

No

Yes

No

No

No

No

No

No

No

No

No

No

Oral sphere

Dysphagia/Velopharyngeal insufficiency

No

Yes

No

n/a

Yes

No

No

Yes

No

No

n/a

n/a

n/a

n/a

Liver

Hepatomegaly

No

No

No

Yes

No

No

No

No

No

No

No

No

No

No

Pancreas

Steatorrhea/Exocrine insufficiency

Yes

n/a

n/a

n/a

No

Yes

Yes

Yes

No

No

n/a

n/a

n/a

n/a

Eye

Cataract

No

No

No

Yes

No

No

No

No

No

No

No

No

No

No

Other

No

No

No

No

No

No

No

Shallow orbits with mild restriction of medial rectus action OU; right macular pigmentary changes

No

Corneal thickness

No

No

No

No

Blood test

SCK (UI/l) (maximum)

N

460

n/a

500

340

370

N

372

n/a

N

n/a

n/a

n/a

n/a

Blood count abnormalities (maximum)

Eosinophilia 1.5 × 10e9/L

N

n/a

N

Eosinophilia 0.8 × 10e9/L

N

Eosinophilia 0.9 x 10e9/L

PLT count: 78 x 10e9/L, MCV: 98.4 fL

N

N

n/a

n/a

n/a

n/a

Liver function

n/a

N

n/a

Cholestasis

n/a

SGOT: 63 IU/L (<53); SPGT: 56 IU/L (<36); ALP: 308 IU/L (<335); GGT: 53 IU/L (<26)

SGOT:210 IU/L (<40); SGPT: 151 IU/L (<35); ALP: 772 IU/L (<315); Bili: 33 mmol/l (<14)

SGOT: 100 IU/L (<38); SGPT: 132 IU/L (<41); ALP:129 IU/L (<129); GGT:106 IU/L (<58)

n/a

n/a

n/a

n/a

n/a

n/a

Muscle exploration

EMG: myogenic

Yes

n/a

n/a

Yes

Yes

n/a

n/a

N

n/a

n/a

n/a

n/a

n/a

n/a

MRI/CT-scan

Adiposis (MRI)

Adiposis (MRI)

n/a

n/a

n/a

n/a

n/a

Atrophy of paraspinal and rectus abdominis muscles (CT scan)

n/a

Adiposis (MRI)

n/a

n/a

n/a

n/a

Lung exploration

PFT (pulmonary Function Test): Restrictive syndrome

Yes (asthma)

Yes

n/a

n/a

Yes

n/a

Yes

Yes

Yes (poor participation)

Yes

Yes

Yes

Yes

No

- FVC (% of predicted)

1.61 L (83 %)

1.82 L (42 %)

n/a

n/a

38 %

n/a

53 %

64 %

1.33 L (86 %)

1.47 L (36 %)

78 %

n/a

34 %

91 %

- FEV1 (% predicted)

1.25 L/min (73 %)

2.02 (44 %)

n/a

n/a

n/a

n/a

56 %

n/a

1.32 L/min (101 %)

1.15 L/min (34 %)

n/a

n/a

37 %

n/a

- FEV1/FCV (%)

78 %

111 %

n/a

n/a

n/a

n/a

N

n/a

99 %

78 %

86 %

n/a

90 %

76 %

- DLCO

n/a

41 %

n/a

n/a

51 %

n/a

n/a

n/a

0.87 (64 %)

Not feasible

67 %

n/a

34 %

88 %

PET/CT-scan

n/a

No pulmonary fibrosis (CT scans)

n/a

n/a

No fibrosis

n/a

No fibrosis

No pulmonary fibrosis; presence of a nodule

n/a

Pulmonary fibrosis, slightly hypermetabolic lesions

n/a

n/a

n/a

n/a

Pathology

Peripheral muscle

Adiposis

Dystrophy, fibrosis, adiposis

n/a

Dystrophy, fibrosis, adiposis

Fibrosis, adiposis

n/a

n/a

Fibroadipose replacement, endomysial fibrosis, atrophic and hypertrophic fibers, central nuclei

n/a

n/a

n/a

n/a

Fatty infiltration

n/a

Skin

Sclerodermiform aspect, Elastin anomalies

n/a

n/a

n/a

RTS-like

n/a

Hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, spongiosis. Numerous apoptotic keratinocytes.

n/a

n/a

n/a

n/a

n/a

Sclerodermiform aspect, fibrosis, elastic tissue degeneration

n/a

Visceral organs

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Pulmonary fibrosis

Pulmonary, esophageal and mediastinal lymph node fibrosis, pancreas fatty infiltration

n/a

Vasculature

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Elastic degeneration, medial calcification

n/a

Gene analysis

RECQL4

No mutation

No mutation

n/a

No mutation

No mutation

No mutation

No mutation

No mutation

No mutation

No mutation

n/a

No mutation

No mutation

n/a

Other genes

No

CAPN3, LMNA, CAV3 (no mutation)

No

No

SMN1 (no mutation)

No

No

CLCN1- c.2509-3C > T (intronic between exons 22 and 23); c.2926 C > T (p.976 R > X, nonsense mutation)

No

No

No

No

No

No

FAM111B

c.1879A > G (p.Arg627Gly)

c.1879A > G (p.Arg627Gly)

c.1879A > G (p.Arg627Gly)

c.1879A > G (p.Arg627Gly)

c.1883G > A (p.Ser628Asn)

c.1883G > A (p.Ser628Asn)

c.1883G > A (p.Ser628Asn)

c.1883G > A (p.Ser628Asn)

c.1874C > A (p.Thr625Asn)

c.1289A > C (p.Gln430Pro)

c.1861 T > G (p.Tyr621Asp)

n/a

c.1861 T > G (p.Tyr621Asp)

c.1861 T > G (p.Tyr621Asp)

Inheritance

De novo

De novo

Paternal inheritance

n/a

No maternal inheritance

De novo

De novo

De novo

de novo

n/a

Paternal inheritance

n/a

Paternal inheritance

Paternal inheritance