The clinical symptoms of MWS can be classified as follows:

Hirschsprung and Mowat-Wilson

Hirschsprung’s disease (HSCR) is a polygenic disorder that can be considered as a disease independently or as one of the symptoms of another disease. The genes involved in this disease can include SOX10, NRTN, GEMIN2, ZEB2, GDNF, and many other genes that cause diseases such as metastatic melanoma, Megacolon, MWS, etc. [25,26,27]. The most crucial symptom of HSCR is intestinal disorders, which can range from mild to severe and must be confirmed by intestinal biopsy. The treatment of HSCR can be the isolation of the part of the intestine with an abnormality or an intestinal transplant. HSCR is seen in more than 40% of people with MWS as a secondary disease in association with the primary disease, or better words, as one of the main symptoms of MWS [3, 28,29,30,31].

Growth parameters

Usually, the three parameters that are measured to check the growth status of people with MWS include height, weight, and head circumference. At birth, growth parameters are usually in the normal range. However, from age 7, developmental problems gradually appear, and with increasing age, the difference between affected and non-affected people in the population increases. The average birth weight for these people is between 3200 and 3800 g, the average height is between 45 and 55, and the average head circumference is between 30 and 36 cm. It should be noted in the diagnosis that the head circumference of babies may be smaller than expected, but there is no microcephaly [32]. However, microcephaly is common in these patients and is seen in about 80% of cases. Most adult patients are under 150 cm tall and 50 kg in weight. One of the distinctive features of people with MWS is having a thin body, but the fit of the body is there to some extent. This narrowness can also be due to a lack of weight and BMI in affected people. Charts related to the height and weight growth of children with MWS should be provided to the pediatrician from the very beginning so that necessary measures can be taken to minimize the height and weight problems. Also, the growth charts help the doctor examine the clinical investigations related to the disease and deviation from the typical growth pattern [33].

Neurological symptoms, developmental delay, and behavioral characteristics

The mutations in the genes responsible for MWS disease can have extensive effects on the nervous system. For example, it disrupts the development of the axons and the neural tube of the fetus in the early stages, so the abnormalities related to the nervous system and brain are one of the most important These are the symptoms that the doctor should consider in the examination of patients with MWS. For example, if the expression of the Fibroblast Growth Factor 9 gene is inhibited in the six-layered cortex, it leads to a decrease in the growth of nerve progenitor cells [34]. In addition, when the transcription of secreted frizzled related protein 1, located in the anterior part of the brain, is suppressed by MWS disease mutation, it increases the apoptosis of corpus callosum cells. It is also possible that astrocytes such as Bergmann glia become abnormal, and as a result, a person with MWS shows symptoms such as moderate-to-severe mental retardation [35,36,37,38,39].

Among other neurological symptoms, it is possible to refer to multiple episodes of epilepsy and sleep disorders, which are seen in about 80% of affected people and are probably due to defects in nerve cells that need GABA transmitters for their activity. Agenesis of the corpus callosum and poor hippocampal formation are observed in about 45% and 15% of patients, respectively. In these patients, the brain’s lateral ventricles may expand, resulting in changes such as ventriculomegaly. Cortical atrophy with less prevalence may be present [40,41,42].

Developmental delay in patients is usually diagnosed with hypotonia, which is present in more than 90% of patients. Also, the time of sitting, walking, and talking in affected people has been estimated after two years, after three years, and after five years, respectively, although they may never be able to walk or talk well [43].

In many cases, psychotic symptoms have been observed, probably related to the disorder of neurons related to GABA transmitters, for example, unexplained laughter, symptoms similar to bipolar and schizophrenia, and social personality [44,45,46].

Heart problems

Heart problems are seen in more than half of affected cases, and it can be said that it is one of the common symptoms in MWS patients, although congenital heart symptoms are not the same in all of these people differ from person to person. Among these, the pulmonary artery is one of the cases that can be more involved. For example, in affected people, the pulmonary arteries or the valves that control the blood flow between the heart and the lungs may not be formed, or they may be narrowed due to disorders related to MWS. These abnormalities can cause complications such as pulmonary atresia and peripheral pulmonary stenosis [47, 48].

Another thing that can be mentioned is aortic valve stenosis, which can reduce blood flow or block it, so it must be evaluated in the initial examinations. Also, the aorta may not develop properly or be narrower than usual. Abnormality of the shape of the aorta has also been seen in some patients, where the aortic valve has two cusps instead of three [49,50,51].

In patients with MWS, ventricular septal and atrial septal defects may also be present. Also, mitral valve defect and tetralogy of fallot are other congenital heart complications in sufferers [52, 53].

Musculoskeletal abnormalities

People with MWS, mostly, and more than 90%, have a narrow body, and spinal deviation in the form of scoliosis is standard in them. One problem that falls under the musculoskeletal abnormalities category is delayed bone age. This means that when the age of patients with MWS disease increases, their age and bone growth do not increase in the same direction, but it is a much slower process than healthy people in society [33, 36, 53, 54]. Checking the bone age is considered one of the measured criteria for checking the growth and maturity of people, and it can be easily measured with an X-ray or MRI. Of course, when diagnosing, it should be noted that the delay in the bone age of a person can have many reasons and is not only specific to MWS. For example, endocrine abnormalities or disorders related to the thyroid gland can also lead to this disorder. Intra-sutural bones are another bone abnormality that may be seen in MWS people. However, it is not specific to this syndrome as in the previous case because it is also seen in many other diseases such as Osteogenesis imperfecta, Down syndrome, and rickets. In this case, if an additional bone fragment is seen in one of the joints in the skull, the patient may suffer from this condition [8, 55].

The subsequent disorder in this category is chest problems, among which pectus excavatum can be mentioned. This disorder causes depression in the chest and thorax, which overlaps with Marfan’s syndrome and is one of the main symptoms of Marfan’s syndrome if it is not a specific symptom of MWS disease. In this case, due to the depression in the chest, the normal function of the heart and lungs may be affected, so it is imperative to quickly diagnose this symptom because it may affect vital organs and endanger the health and life of the affected person [6, 47, 53]. Unlike pectus excavatum, which causes depression, another symptom can be pigeon chest protrusion of the sternum and chest. The side effects of this condition are not as severe as the previous one, but the heart and lungs are still affected, and it may cause complications such as shortness of breath.

Skeletal problems related to the foot in MWS sufferers are more common than other skeletal problems but have fewer side risks. For example, the bunion is a complication related to the big toe, which causes it to bend toward the other toes. Eventually, it can be a little painful or make walking difficult for these people. MWS patients may also have double toes [56]. Sometimes the toes are unusually long, about twice the length of the toes of a healthy person, which is similar to Marfan’s syndrome and homocystinuria. Flat soles may also be observed, which a small percentage of patients suffer from.

Meanwhile, one of the foot problems that can cause more pain is calcaneovalgus, which causes the affected person’s ankle to be deformed and the ankle to bend inward so that the toes touch the leg. Although this problem is not common, it can cause severe problems in walking if left untreated. It should be noted that the correct diagnosis should be made in this case because this symptom can also be seen in other diseases, such as myelomeningocele and polio, and is not specific to MWS. Flat soles and clubfoot have also been reported in several cases [57].

The affected person may be unable to bend his fingers well due to complications in the proximal interphalangeal joint. The thumb of these people is short, comprehensive, and crooked, while the other fingers are long and elongated; they may also have an extra thumb. It is also possible that the finger joints of their hands are protruding [53].

Dislocation of the patella from its natural position is one of the complications seen in MWS patients. In addition, knock-knee may occur, in which the knees come into contact with each other, but at the same time, the soles of the feet are much further apart than usual, and they become crossed. About 75 to 90 percent of patients have abnormal knee abnormalities [55].

Abnormalities in the neck up

Affected people have a square face, protruding forehead, and circular skull. These people usually have a triangular chin and a small jaw. A small jaw is a problem that may not seem acute, but it is likely to disturb breathing, so treatment measures should be taken for this problem quickly. Eyebrows have a continuous state, where they are joined together, broad, and thick, and as they are separated, the eyebrow hairs become thinner and more scattered [58, 59].

As it was said, these people have developmental delays, affecting things like teething and causing teeth to grow later. Also, if the teeth grow, they are crowded and disorganized and are placed at a long distance from each other. Ear abnormalities can occur in otitis media and hearing loss, which can occur in about 35 to 40 percent of affected people [56, 60].

Eye problems are observed in less than ten percent of cases. However, various eye complications observed in patients can occur from mild to severe. For example, coloboma of the iris or retina also overlaps with Charge’s syndrome. Another thing is that these people sometimes have smaller eyes than usual, and it is possible for them to have problems like myopia or astigmatism. In some cases, it has been seen that the color of the affected person’s iris is different. For example, one is dark, and the other is blue. Nevertheless, more severe cases can be a wide drooping of the eyelid, which sometimes disturbs the vision. It is also possible that the pupils of the two eyes are not aligned and deviate [61, 62].

The lips of these people have a one-sided or two-sided gap with a broad lower lip and an upper lip shaped like the letter M. In addition to these, sometimes the affected person’s tongue is not in the right place since the newborn period, which is a problematic case and can block the airway or make it difficult for him to swallow. The tip of the nose is prominent, bent downward, and has an eagle shape, and the distance between the nostrils is considerable. In addition, the distance between the upper lip and the nose has also increased. The baby may produce a strange and abnormal sound when breathing while awake or sleeping, probably due to an abnormality in the vocal cords, which may be due to a problem in the tissue of the larynx, which, of course, needs to be examined by a doctor [6, 53, 60, 63,64,65]. Visible symptoms are shown in Fig. 3.

Fig. 3

Image related to MWS facial features. (Note: out of respect for patients’ rights, this image is not related to a real person and is designed by the software)

Skin abnormalities

The presence of many wrinkles in the palms and feet of the affected person can be one of the skin symptoms that appear in them. However, it should be noted that this symptom overlaps with Costello’s syndrome, and a dermatologist should make the diagnosis accurately. Sometimes, it is also possible that some areas of the skin lack pigment [16].

Genital and urinary abnormalities

In male patients, one of the testicles may be missing, and the urinary-genital duct may be defective and not formed properly. Also, sometimes it has been observed that the scrotum is divided into two parts or that the skin of the testicles sticks to the trunk of the genital organ [66].

The presence of two kidneys or kidneys with an abnormal shape and the return of urine between the kidney and the bladder are other cases seen in a small percentage of affected people. All these cases can be detected by ultrasound [67].

Other abnormalities

Secondary cases of the disease include the absence of a spleen, frequent vomiting attacks, and the presence of an extra nipple in the middle of the chest [68].